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Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures
Journal Pre-proof Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures Anne Slavotinek, Johanna M. van Hagen, Louisa Kalsner, Shashidhar Pai, Laura Davis-Keppen, Lisa Ohden, Yvonne G. Weber, Erica L. Macke, Eric W. Klee, Eva Morava, Lauren Gunderson, Richard Person, Shuxi Liu, Marjan Weiss PII:
S1769-7212(19)30125-9
DOI:
https://doi.org/10.1016/j.ejmg.2020.103850
Reference:
EJMG 103850
To appear in:
European Journal of Medical Genetics
Received Date: 17 February 2019 Revised Date:
26 November 2019
Accepted Date: 12 January 2020
Please cite this article as: A. Slavotinek, J.M. van Hagen, L. Kalsner, S. Pai, L. Davis-Keppen, L. Ohden, Y.G. Weber, E.L. Macke, E.W. Klee, E. Morava, L. Gunderson, R. Person, S. Liu, M. Weiss, Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures, European Journal of Medical Genetics (2020), doi: https:// doi.org/10.1016/j.ejmg.2020.103850. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Masson SAS.
Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures
Anne Slavotinek1*, Johanna M van Hagen2, Louisa Kalsner3, Shashidhar Pai4, Laura Davis-Keppen5, Lisa Ohden6, Yvonne G. Weber7, Erica L. Macke8, Eric W. Klee8, 9, Eva Morava8, 9, Lauren Gunderson9, Richard Person10, Shuxi Liu10, Marjan Weiss2
1 = Dept. Pediatrics, Division of Genetics, University of California, San Francisco; San Francisco, CA, 941432711 2 = Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan 1117, Amsterdam, The Netherlands 3 = Departments of Pediatrics and Neurology, Connecticut Children’s Medical Center and University of Connecticut Health Center, Farmington, CT 4 = Medical Univerasity of South Carolina Health, Charleston, South Carolina 5 = University of South Dakota Sanford School of Medicine and Sanford Children’s Hospital, Sioux Falls, SD 6 = Sanford Children’s Hospital and Specialty Clinic, Sioux Falls, SD 7 = Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 8 = Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA 9 = Department of Clinical Genomics, Mayo Clinic, Rochester MN, USA 10 = GeneDx, Gaithersburg, MD
* = Corresponding author Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711 Tel: 415 476 2757 Fax: 415 476 9305 Keywords: Jumonji domain-containing protein 1C, JMJD1C, autism spectrum disorder, intellectual disability
1
Abstract The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed.
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Introduction The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) which a member of the jmJC domain-containing protein family that is involved in histone demethylation (Guo et al., 2015; Sáez et al., 2016). The gene is widely expressed in the brain. In response to DNA damage, JMJD1C interacts with Ring finger protein 8 (RNF8) and demethylates the mediator of DNA damage checkpoint protein 1 (MDC1) at Lys45, promoting an interaction between MDC1 and ring finger protein 8 (RNF8) that results in RNF8-mediated ubiquitylation of MDC1 around double strand break sites (Lu and Matunis, 2013; Watanabe et al., 2013). De novo, deleterious sequence variants in JMJD1C have been previously reported in a patient with a phenotype resembling classical Rett syndrome and in two patients with autism spectrum disorder (Neale et al., 2012; Iossifov et al., 2014; Sáez et al., 2016). Functional studies were performed for the missense variant, p.(Pro163Leu), that was identified in the patient with manifestations similar to Rett syndrome and the altered protein demonstrated abnormal subcellular localization, reduced MECP2 binding and reduced ability to demethylate MDC1. Two other case reports described chromosome aberrations disrupting or causing haploinsufficiency for JMJD1C in children with intellectual disability (Castermans et al., 2007; Shimojima et al., 2017). However, the full extent of the phenotypic features and spectrum of deleterious variants in this gene are unknown. Herein we report seven, unrelated patients with developmental delays or intellectual disability and de novo, heterozygous sequence variants in JMJD1C.
Clinical reports Clinicians were contacted after matching in GeneMatcher (Sobreira et al., 2015). Written informed consent for sequencing was obtained from all patients. Medical history and phenotypic features were extracted from health records as per standard clinical practice. Patient 1 Patient 1 was a male who was 11 years and 11 months old at the time of reporting. He was the second child of healthy, non-consanguineous parents. The pregnancy was uncomplicated and he was delivered at 40 weeks of gestation with the umbilical cord around the neck and with meconium staining of the amniotic fluid. 3
Birthweight was 3,750 g (50-75th centile) and length was 56 cm (>97th centile). Apgar scores were 8 and 10 at one and five minutes respectively. The neonatal period was notable for frequent crying and reflux. He had strabismus, but his vision and hearing were normal. His milestones were delayed and he first walked independently at two years of age and spoke his first words at two and a half years of age, resulting in diagnoses of intellectual disability, autism spectrum disorder and attention deficit hyperactivity disorder. At 14 years of age, WISC-III showed a verbal IQ of 82 (range 76-91), performance IQ of 71 (range 66-86) and a total IQ of 75 (range 69-84). On examination at 11 years and 11 months of age, occipitofrontal circumference (OFC) was 55 cm (+0,53 SD; length was 158cm (mean to +0,42 SD ); and weight was 37 kg (-1,80 SD, weight/length). There were no dysmorphic features. A magnetic resonance imaging (MRI) scan of the brain was not performed. Patient 2 Patient 2 was delivered at 39 weeks of gestation to a 36 year old, G3P2-3 mother with a birthweight of 3,005 g (10-25th centile). The baby had hypotonia early in life that has slowly improved and she first walked independently at 18 months of age. Her speech was delayed and she had full sentences in first grade. She received special education with occupational therapy and adaptive physical education from two years of age until 4th grade and she was around one year behind her peers when she started Kindergarten. She also received resource classes for 1.5-2 hours per day at school. A developmental assessment at 10 years of age showed a verbal comprehension score of 87 (19th centile), perceptual reasoning score of 75 (<1st centile), working memory sore of 74 (4th centile) and a processing speed score of 56 (<1st centile). She has received diagnoses of mild to moderate intellectual disability although her verbal comprehension score was in the normal range as above, attention deficit hyperactivity disorder (ADHD) combined type, and developmental coordination disorder. She has had difficulties with mood regulation, anger management and anxiety that has been treated with methylphenidate. At 12 years of age, she was in 6th grade and had strengths in reading and writing. She tested at average and below average for the state standards. She was diagnosed with dyscalculia and had difficulty with focusing, telling the time and understanding money. A tight frenulum, narrow palate and difficulties with articulation were noted in early childhood and a tonsillectomy and adenoidectomy were performed for sleep apnea and snoring. She continues to have encopresis several times per week. She has not 4
had menstrual periods. In the family, her oldest brother showed signs of depression at 17 years of age and a maternal aunt was diagnosed with bipolar disorder. Ethnicity was European Caucasian for both parents and there was no known consanguinity. On examination, she was conversant with hesitant speech. Her height was 165 cm (92nd centile) and weight was 42.4 kg (41st centile). OFC was 54.2 cm (75-90th centile). She had a short columella, open mouth and a high arched palate. There was arachnodactyly of her thumbs, fingers and toes and right 3rd finger measured 8.5 cm (>97th centile). She had mild elbow contractures. She had mild hypotonia, but there were no other neurological signs. Patient 3 Patient 3 was a 5-year-old boy who was non-verbal. He was diagnosed with severe autism spectrum disorder following loss of words and regression between the ages of two and three years. He was born prematurely at 29.5 weeks of gestation and remained in the neonatal intensive care unit for six weeks. He was not dysmorphic and had normal growth parameters. He had a normal 24 hour electroencephalogram (EEG) that was performed due to concerns regarding regression. A brain MRI scan showed no structural malformations. Patient 4 Patient 4 was born at 30 weeks gestation to a 34 year old, G4P2Ab2 mother. Birthweight was 1,265 g (10-25th centile). He had unilateral, left-sided complete cleft lip and palate that was repaired without complications. A cranial ultrasound scan showed grade 1 intraventricular hemorrhage, but was otherwise normal. He remained in the neonatal intensive care unit for 41 days and was followed regularly in the high risk infants clinic after discharge. Developmental delays were noted in his second year of life and he was evaluated in genetics clinic at 3 years of age. He had a prominent forehead and flattening of the midface associated with his clefting, but his examination was otherwise normal. A karyotype and array comparative genomic hybridizarion were normal. He was admitted for suspected seizure like activity, but an EEG, including extended video monitoring, showed no epileptic pattern. He was last seen at four years of age. Growth parameters were in the normal range and his facial features were unchanged. Motor skills were normal, but he continued to have mild speech and language delays and was receiving speech therapy, physical therapy and occupational therapy. Patient 5 5
Patient 5 was a male who was delivered at 39 weeks gestation. Birthweight was 4,167 g (99th centile) and length was 53 cm (95th centile). Significant hypotonia was noted after birth and he was diagnosed with dilated cardiomyopathy. He had a Berlin ventricular assist device prior to transplant. During the time he had the Berlin, he developed a clot with emboli and subsequently suffered strokes. He had had seizures around the time of his strokes and was started on an anticonvulsant. He underwent heart transplantation at 3 months of age. Brain MRI at age 2 years revealed chronic infarctions in both cerebral hemispheres, including in the left parietal lobe, left temporal occipital region, and right frontal lobe. EEG at age 2 years was abnormal, but considered referable to the known history of bihemispheric stroke. He had hypotonia, hypermobility, and gross motor delay. He walked at 2.5 years and talked at 2 years. At 6 years of age he had to crawl up stairs, could not jump, was unable to pedal a tricycle, and had an atypical walk and run. The child has not had IQ testing, but he does carry a diagnosis of ADHD. At the time of diagnosis, he was in kindergarten and received physical therapy and occupational therapy. On physical exam, no dysmorphic features were noted. He had short stature, decreased muscle tone, joint hypermobility, pronation of the feet, and a wide-based gait. He had a chronic history of feeding difficulties and at age 6 was on nasojejunal feedings. Patient 6 Patient 6 was a female born at 38 weeks of gestation. Her mother reportedly suffered from epileptic seizures in early childhood, but was not treated with medications. The child had normal developmental milestones, with indepedent walking at 14 months of age and first words at 18 months of age. Her speech development was delayed and she received speech therapy and went to a mainstream kindergarden. At 4 years of age, she presented with nocturnal, generalized tonic-clonic seizures. An EEG showed centro-temporal epileptic discharges. Therapy with sulthiame was commenced but did not completely control the seizures. Patient 7 Patient 7 was a 2 year old female who presented with seizures at 4 months of age. She has been diagnosed with intractable epilepsy of unknown etiology. An EEG at 8 months of age showed non-specific left temporal slowing and multifocal epileptiform discharges. Electrographic seizures were recorded occasionally with clinical accompaniment and were characterized by generalized polyspike and wave activity followed by 6
generalized decrement. A follow up EEG at 13 months of age showed bitemporal slowing, bitemporal and bioccipital synchronous and independent epileptiform discharges. A brain MRI at 4 months of age showed no abnormalities. A follow up MRI at 21 months also showed no structural abnormalities. She has exhibited significant developmental delays. From a gross motor standpoint, she sat independently at 2.5 years of age. She cannot stand without support and was not taking independent steps. From a fine motor perspective, she could reach for objects and transfer them between her hands. She had developed a pincer grasp. From a speech and language standpoint, she had no words at 2.5 years of age. She had generalized hypotonia that was symmetrical. At two years of age, she began developing laughing spells and started biting her feet and toes and other people.
Materials and Methods Exome sequencing was performed with a trio approach on probands and both biological parents for all patients. All sequence variants are described with reference to JMJD1C transcripts NM_032776.2/ NM_001322252. Exome capture for Patient 1 was done using the SeqCap EZ Exome Probes v3.0 (Roche Sequencing, Pleasanton, USA). Exome libraries were sequenced on an Illumina HiSeq instrument (Illumina, San Diego, USA) with 151bp paired-end reads at a median coverage of 100x. Sequence reads were aligned to the hg19 reference genome using BWA Variants were subsequently called by the GATK unified genotyper, and annotated using a custom diagnostic annotation pipeline. A de novo approach was applied for candidate gene identification. For patients 2, 3, 4, 5 and 7 who underwent WES as a clinical test, sequencing technology and the variant interpretation protocol have been previously reported (Tanaka et al., 2015). Bi-directional sequence reads were assembled and aligned to reference sequences based on NCBI RefSeq transcripts and human genome build GRCh37/UCSC hg19. Using a custom-developed analysis tool (XomeAnalyzer), data were filtered and analyzed to identify sequence variants and most deletions and duplications involving three or more coding exons (Retterer et al., 2015). Reported clinically significant variants were confirmed by an appropriate orthogonal method in the proband. Sequence and copy number variants were reported according to the Human Genome Variation Society (HGVS) or International System for Human Cytogenetic Nomenclature (ISCN) 7
guidelines, respectively. Reportable variants include pathogenic variants, likely pathogenic variants and variants of uncertain significance. Likely benign and benign variants, if present, were not routinely reported. For Patient 6, WES was performed as a trio with her biological parents at the Institute of Clinical Molecular Biology at the University of Kiel and the Cologne Center for Genenomics (https://varbank.ccg.uni-koeln.de) using the Nextera Rapid Capture Expanded Exome Kit and the Illumina HiSeq2500. The data were analyzed with a standardized pipeline as reported previously (Helbig et al., 2019).
Results A summary of the clinical features of these seven patients is provided in Table 1. The variants in JMJD1C are shown in Table 2 and are not redescribed in the text. In Patient 2, a heterozygous, de novo variant, c.833delC, predicted to result in p.(Pro278Leufs*102), was also identified in the SRCAP gene. This variant has not been seen in public databases and was also predicted to be pathogenic by the reporting laboratory. Nonsense or frameshift variants that result in the formation of a C-terminal-truncated SRCAP protein miss critical functional domains and act as dominant negative mutations that cause Floating Harbor syndrome (Messina et al., 2016). However, this patient did not have short stature or the facial differences that are typically found in children with FHS. Patient 4 also had a missense variant in CACNA1A, c.5666A>G, predicting p.(Asn1889Ser) that was paternally inherited and classified as a variant of unknown significance. Patient 5 had a second, likely pathogenic variant that was identified in TTN, c.62426-2A>C, that was maternally inherited. This TTN variant is believed to be the cause for the child’s cardiomyopathy and may be contributing to the hypotonia. Patient 6 carried an additional, heterozygous de novo variant in WDR59, c.896A>G, predicting p.(Asp299Gly), that could also be relevant to the seizures and speech delay. Lastly, Patient 7 had 2% heteroplasmy for the m.10197G>A variant, predicting p.(Ala47Thr) in the MT-ND3 gene that was predicted to probably damaging with MutationTaster (p = 0.999). However, the degree of heteroplasmy was considered to be to low to account for the patient’s neurocognitive status.
Discussion 8
Herein we report seven patients with de novo, heterozygous variants in JMJD1C, comprising three missense variants [c.5072A>G, predicting p.(Asn1691Ser), c.1100T>C, predicting p.(Leu367Pro) and c.349G>A, predicting p.(Val117Ile)], two frameshift variants [c.1082_1098del17, predicting p.(Lys361Thrfs*4) and c.326_326delC, predicting p.(Pro109Leufs*3)], mosaicism for a frameshift variant [c.3167_3207del41, predicting p.(Ser1056Cysfs*10)] and mosaicism for an intronic variant [c.5863-6T>G], that was predicted to disrupt splicing. All patients shared neurocognitive phenotypes with developmental delays. Three patients had attention deficit disorders, two had autism spectrum disorder and two patients suffered from seizures. There were no complications in pregnancy or at the birth. Growth parameters were normal and dysmorphic features were mild or absent. There was no individual with a Rett syndrome-like phenotype or autism spectrum disorder as previously described (Neale et al., 2012; Iossifov et al., 2014; Sáez et al., 2016) and all of the patients appeared to have non-specific, neurocognitive differences. All of the variants in JMJD1C were shown to be de novo, with the exception of Patient 7, in whom parents were unavailable for testing. The de novo nature of the variant with confirmed paternity and maternity from exome sequencing constitutes strong evidence for pathogenicity (PS2; Richards et al., 2015). In addition, all of the variants were absent from control databases that constitutes moderate evidence for pathogenicity (PM2; Richards et al., 2015) except for the missense variants in Patient 5. All of the variants were predicted to be disease causing by MutationTaster (Schwarz et al., 2014) and the missense variants were highly conserved (Table 2) with the exception of the variaint in Patient 1, consistent with the criteria for multiple lines of computational evidence that support a deleterious effect on the gene/gene product that constitutes supportive evidence for pathogenicity (PP3; Richards et al., 2015). Patient 3 had mosaicism for a de novo, intronic variant in JMJD1C, c.5863-6T>G in intron 15. This variant was predicted to alter the wildtype donor site to most probably affect splicing (Human Splicing Finder), although variants affecting the same splice site, c.5863-3T>C and c.5863-4G>A, have been found in 12/275676 and 4/244,612 individuals in gnomAD. JMJD1C is under strong constraint for loss of function variants, with 107.7 such variants predicted and only 3 observed (pLI = 1.0; gnomAD). It is possible that the loss of function variants will prove to be more pathogenic than missense variants in this gene, but there are too few patients for analysis at present. Although 9
JMJD1C variants have previously been associated with intellectual disability in some of the patients presented in this report, genetic factors in addition to the the JMJD1C variant may be important in the pathogenesis of the neurocognitive phenotype. Two patients had additional variants in genes known to be associated with intellectual disabililty, including SRCAP (Messina et al., 2016) and CACNA1A (Reinson et al., 2016). Somatic mosaicism was present for two variants (Table 2). For two patients, the nucleotide substitution has been found as a heterozygous variant in gnomAD (Table 2). One of the patients also had a likely pathogenic variant in TTN, a gene associated with cardiomyopathy and/or skeletal muscle myopathy and another had a variant in WDR59 that was considered a more likely explanation of the phenotype. The last patient was heteroplasmic for a pathogenic mitochondrial variant. JMJD1C was first studied as TRIP8, a member of the TRIP1 to TRIP15 family of genes that encode thyroid hormone receptor beta (TR beta)-binding proteins (Katoh and Katoh, 2003). The gene has 26 exons that encode a 2,540 amino acid protein with two bipartite nuclear localization signals (codons 352-368 and 2,3652,381), a TRI8H1 domain (codon 1,697-1,873), TRI8H2 domain (codon 2,057-2,351) and a JMJC domain (codon 2,387-2,486; Katoh and Katoh, 2003). As JMJC domain proteins are implicated in chromatin remodeling, TRIP8 was predicted to be a transcriptional regulator associated with nuclear hormone receptors (Katoh and Katoh, 2003). TRIP8 interacts with T3 receptor β in a T3-dependent manner, but could also interact with the retinoid X receptor (RXR) and other transcription factors, including the vitamin D receptor, peroxisome proliferation-activated receptor (PPAR)-α and PPAR-γ and retinoic acid receptor (RAR)-α (Lee et al., 1995; Yuan et al., 1998). The first report of disruption of the JMJD1C gene in association with a phenotype concerned a nine-year old male who was evaluated for impairment in social and communication skills (Castermans et al., 2007). His milestones were normal, but early language and social development were delayed and he did not develop fantasy or pretend play and did not socialize with his peers. An assessment showed deficits in social reciprocity, impairment of non-verbal communication, mild delays in expressive and receptive language and marked impairment in social perspective taking. He fulfilled the DSM-IV criteria for the diagnosis of highfunctioning autistic spectrum disorder despite a normal intelligence quotient (Castermans et al., 2007). This 10
child carried a de novo, balanced paracentric inversion [46,XY,inv(10)(q11.1;q21.3)], in which the distal breakpoint interrupted the first intron of JMJD1C and was predicted to disrupt both the TRIP8a and TRIP8b transcripts, with possible preservation of an alternative TRIP8c transcript (Castermans et al., 2007). Subsequent large-scale sequencing studies on children with autism spectrum disorders revealed additional heterozygous, de novo variants in JMJD1C. In a study performing trio exome sequencing on patients with autism spectrum disorder, one missense variant, p.(Val1070Ile), and one nonsense variant, p.(Arg69*) in were identified (Neale et al., 2012; Iossifov et al., 2014). Another study examined 215 patients presenting with autism spectrum disorder, intellectual disability and Rett syndrome without known genetic defects and detected seven nucleotide variants clustering in exon 10 of JMJD1C that were not present in control databases (Sáez et al., 2016). Two of these variants were considered to be pathogenic, including a heterozygous, de novo variant, c.488C>T, predicting p.(Pro163Leu), in a 29 year old female who was diagnosed with classical Rett syndrome (Sáez et al., 2016). This patient demonstrated loss of social interaction at 18 months of age and additional findings of delayed speech development, gait dyspraxia, hand-washing stereotype, teeth grinding, air swallowing, kyphoscoliosis and tonic epilepsy (Sáez et al., 2016). Although endogenous JMJD1C is present in the cytoplasm, mutant p.(Pro163Leu)-JMJD1C was markedly enriched in nuclear chromatin and was less efficient in demethylating MDC1, a non-histone target of JMJD1C, compared to wildtype JMJD1C (Sáez et al., 2016). In addition, an immunoprecipitation assay demonstrated an interaction between JMJD1C and MECP2, with less efficient binding of the JMJD1C-Pro163Leu mutant protein compared to wildtype JMJD1C, thus potentially explaining the phenotypic overlap between the patient’s phenotype and Rett syndrome (Sáez et al., 2016). Another heterozygous, de novo variant in JMJD1C, c. 3559A>G, predicting p.(Thr1187Ala) was also noted in a male patient with intellectual disability, but was not functionally studied. Deletions including JMJD1C have also been published. A three year old Japanese female who was unable to sit or to crawl and had no single words reported to have a 10.4 Mb deletion at chromosome 10q21.3q22 that spanned 84 RefSeq genes, including CTNNA3 and JMJD1C (Shimojima et al., 2017). This child had Tetralogy of Fallot, hypotonia, growth delays and dysmorphic features comprising hypertelorism, 11
downslanting palpebral fissures, epicanthal folds, a flat nasal bridge, low-set ears and a low hairline with a webbed neck and small hands and feet (Shimojima et al., 2017). However, although haploinsufficiency for JMJD1C was considered as a possible explanation for the phenotype, numerous other genes were also deleted. JMJD1C has also been suggested to be a modifier gene for congenital heart disease (Guo et al., 2015), as sequencing 184 individuals with 22q11.2 deletion syndrome for modifying genetic variants revealed ten rare single nucleotide variants in JMJD1C in nine patients with congenital heart disease that were not present in controls (Guo et al., 2015). However, none of these patients reported here demonstrated cardiac defects.
Conclusion We present seven patients with heterozygous variants in JMJD1C and neurocognitive differences that included learning delays, ADHD, autism spectrum disorder and seizures. There were no other consistent clinical findings. All patients had either mosaicism, a second variant that could be influencing the intellectual disability, or a variant that was found in the heterozygous state in a public database. In the literature, only one JMJD1C variant has undergone functional evaluation. We conclude that further data strengthening the association of JMJD1C variants with neurocognitive deficits is needed. Further reports of patients, functional studies or animal models are still required for a more definitive implication of JMJD1C in the pathogenesis of intellectual disability.
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Acknowledgements We are grateful to the patients and families for their participation.
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Table 1. Clinical features of patients with JMJD1C variants Patient 1 2 Sex/Age at reporting M/11 y 11 m F/12 y Gestation 40 w 39 w Birth parameters th Weight 3,750g (50-75 ) 3,005g (10-25th) Length 56 cm (>97th) NA Neonatal period Gastroesophageal reflux
Development Age at walking Age at first words Neurocognitive Developmental delays ADD/ADHDa Autism Seizures Hypotonia Growth parameters Height Weight Head circumference Dysmorphic features Prominent forehead Flat midface Short columella Open mouth Narrow palate Musculoskeletal Arachnodactyly Elbow contractures Other Strabismus Investigations MRIb brain c
EEG
2y 2.5 y
18 m 6y
+ +
+ + -
3 M/5 y 29.5 w
4 M/4 y 30 w
5 M/6 y 39 w
6 F/4 y 38 w
7 F/2 y 36 w
NA NA
1,265g (10-25th) NA Left cleft lip/palate Intraventricular hemorrhage
4,167g (90-97th) 53 cm Dilated cardiomyopathy; strokes secondary to treatment; seizures secondary to strokes
NA NA
2,400g (10-25th)
NA NA
NA NA
2.5 y 2y
14 m 18 m
-
+
+ + -
+
+ 158 cm (+0.42 SD) 37 kg (-1.8 SD) 55 cm (+0.53 SD)
165 cm (92nd) 42.4 kg (41st) 54.2 cm (75-90th)
+ +
+ +
NA NA NA
80.5 cm (3rd) 10.1 kg (2nd) NA
+ NA NA NA
NA NA NA
103 cm (0.2nd) 21.6 kg (50th) 51.4 cm (46th)
NA
+ +
+
+ + + + + + Not done
Not done
Normal
Not done
Not done
Not done
Normal
Normal
Infarctions (due to Berlin heart), Abnormal (secondary to bihemispheric stroke)
Not done
Normal
Epileptic discharges
Epileptic discharges
Y = years; m = months; w = weeks; NA = not available. ADD/ADHDa = attention deficit hyperactivity disorder; MRIb = magnetic resonance imaging; EEGc = electroencephalogram.
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Table 2. Sequence variants in JMJD1C gene in patients with developmental delays Gene Nucleotide Amino acid ZygosInheritMosaicism Alteration Alteration ity ance
PolyPhen2
Mutation Tas-ter
ExAC browser/ 1000 genomes
gnomAD
ConserVation*
Patient 1 JMJD1C; c.5072A>G p.(Asn1691Ser) Het. de novo B; 0 DC; 1/30,978; Pt, Mm, Gg, Xt NM_001322252.1 p=1 3.228e-5 Patient 2 JMJD1C; c.3167_3207 p.(Ser1056Cysfs*10) Het. de novo Y NA DC; NA NM_001322252.1 del41 p=1 Patient 3 JMJD1C; c.5863NA Het. de novo Y NA DC; NA NM_001322252.1 6T>G p=1 Patient 4 JMJD1C; c.1082_1098 p.(Lys361Thrfs*4) Het. de novo NA DC; NA NM_001322252.1 del17 p=1 Patient 5 JMJD1C; c.1100T>C p.(Leu367Pro) Het. de novo PD; 0.983 DC; p = 3/267030; Pt, Mm, Mmus, NM_032776.2 0.999 1.123e-5 Gg, Dr, Xt Patient 6 JMJD1C c.349G>A p.(Val117Ile) Het. de novo B; 0.012 DC; p = Pt, Mm, Mmus, NM_032776.2 0.983 Gg, Dr Patient 7 JMJD1C c.326delC p.(Pro109Leufs*3) Het. Not NA DC; p = 1 Pt, Mm, Mmus, NM_032776.2 known Gg, Dr Conservation* = amino acid residue conservation in different species as determined from MutationTaster: Pt = Pan troglodytes; Mm = Macacca mulatta; Mmus = Mus musculus; Gg = Gallus gallus; Tr =Takifugu rubripes; Dr = Dario rerio; Xt = Xenopus tropicalis. Het. = heterozygosity; B = benign; DC = disease causing; NA = not applicable; PD = probably damaging.
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Anne Slavotinek: Conceptualization, Resources, Writing – original draft, Writing – review and editing. Johanna M van Hagen: Resources, Writing – original draft, Writing – review and editing. Louisa Kalsner: Resources, Writing – original draft, Writing – review and editing. Shashidhar Pai: Resources, Writing – original draft, Writing – review and editing. Laura Davis-Keppen: Resources, Writing – original draft, Writing – review and editing. Lisa Ohden: Resources, Writing – original draft, Writing – review and editing. Yvonne G. Weber: Resources, Writing – original draft, Writing – review and editing. Erica L. Macke: Resources, Writing – original draft, Writing – review and editing. Eric W. Klee: Resources. Eva Morava: Resources. Lauren Gunderson: Resources. Richard Person: Investigation. Shuxi Liu: Investigation. Marjan Weiss: Resources, Writing – original draft, Writing – review and editing.
S1769-7212(19)30125-9
DOI:
https://doi.org/10.1016/j.ejmg.2020.103850
Reference:
EJMG 103850
To appear in:
European Journal of Medical Genetics
Received Date: 17 February 2019 Revised Date:
26 November 2019
Accepted Date: 12 January 2020
Please cite this article as: A. Slavotinek, J.M. van Hagen, L. Kalsner, S. Pai, L. Davis-Keppen, L. Ohden, Y.G. Weber, E.L. Macke, E.W. Klee, E. Morava, L. Gunderson, R. Person, S. Liu, M. Weiss, Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures, European Journal of Medical Genetics (2020), doi: https:// doi.org/10.1016/j.ejmg.2020.103850. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Masson SAS.
Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures
Anne Slavotinek1*, Johanna M van Hagen2, Louisa Kalsner3, Shashidhar Pai4, Laura Davis-Keppen5, Lisa Ohden6, Yvonne G. Weber7, Erica L. Macke8, Eric W. Klee8, 9, Eva Morava8, 9, Lauren Gunderson9, Richard Person10, Shuxi Liu10, Marjan Weiss2
1 = Dept. Pediatrics, Division of Genetics, University of California, San Francisco; San Francisco, CA, 941432711 2 = Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan 1117, Amsterdam, The Netherlands 3 = Departments of Pediatrics and Neurology, Connecticut Children’s Medical Center and University of Connecticut Health Center, Farmington, CT 4 = Medical Univerasity of South Carolina Health, Charleston, South Carolina 5 = University of South Dakota Sanford School of Medicine and Sanford Children’s Hospital, Sioux Falls, SD 6 = Sanford Children’s Hospital and Specialty Clinic, Sioux Falls, SD 7 = Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 8 = Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA 9 = Department of Clinical Genomics, Mayo Clinic, Rochester MN, USA 10 = GeneDx, Gaithersburg, MD
* = Corresponding author Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711 Tel: 415 476 2757 Fax: 415 476 9305 Keywords: Jumonji domain-containing protein 1C, JMJD1C, autism spectrum disorder, intellectual disability
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Abstract The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed.
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Introduction The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) which a member of the jmJC domain-containing protein family that is involved in histone demethylation (Guo et al., 2015; Sáez et al., 2016). The gene is widely expressed in the brain. In response to DNA damage, JMJD1C interacts with Ring finger protein 8 (RNF8) and demethylates the mediator of DNA damage checkpoint protein 1 (MDC1) at Lys45, promoting an interaction between MDC1 and ring finger protein 8 (RNF8) that results in RNF8-mediated ubiquitylation of MDC1 around double strand break sites (Lu and Matunis, 2013; Watanabe et al., 2013). De novo, deleterious sequence variants in JMJD1C have been previously reported in a patient with a phenotype resembling classical Rett syndrome and in two patients with autism spectrum disorder (Neale et al., 2012; Iossifov et al., 2014; Sáez et al., 2016). Functional studies were performed for the missense variant, p.(Pro163Leu), that was identified in the patient with manifestations similar to Rett syndrome and the altered protein demonstrated abnormal subcellular localization, reduced MECP2 binding and reduced ability to demethylate MDC1. Two other case reports described chromosome aberrations disrupting or causing haploinsufficiency for JMJD1C in children with intellectual disability (Castermans et al., 2007; Shimojima et al., 2017). However, the full extent of the phenotypic features and spectrum of deleterious variants in this gene are unknown. Herein we report seven, unrelated patients with developmental delays or intellectual disability and de novo, heterozygous sequence variants in JMJD1C.
Clinical reports Clinicians were contacted after matching in GeneMatcher (Sobreira et al., 2015). Written informed consent for sequencing was obtained from all patients. Medical history and phenotypic features were extracted from health records as per standard clinical practice. Patient 1 Patient 1 was a male who was 11 years and 11 months old at the time of reporting. He was the second child of healthy, non-consanguineous parents. The pregnancy was uncomplicated and he was delivered at 40 weeks of gestation with the umbilical cord around the neck and with meconium staining of the amniotic fluid. 3
Birthweight was 3,750 g (50-75th centile) and length was 56 cm (>97th centile). Apgar scores were 8 and 10 at one and five minutes respectively. The neonatal period was notable for frequent crying and reflux. He had strabismus, but his vision and hearing were normal. His milestones were delayed and he first walked independently at two years of age and spoke his first words at two and a half years of age, resulting in diagnoses of intellectual disability, autism spectrum disorder and attention deficit hyperactivity disorder. At 14 years of age, WISC-III showed a verbal IQ of 82 (range 76-91), performance IQ of 71 (range 66-86) and a total IQ of 75 (range 69-84). On examination at 11 years and 11 months of age, occipitofrontal circumference (OFC) was 55 cm (+0,53 SD; length was 158cm (mean to +0,42 SD ); and weight was 37 kg (-1,80 SD, weight/length). There were no dysmorphic features. A magnetic resonance imaging (MRI) scan of the brain was not performed. Patient 2 Patient 2 was delivered at 39 weeks of gestation to a 36 year old, G3P2-3 mother with a birthweight of 3,005 g (10-25th centile). The baby had hypotonia early in life that has slowly improved and she first walked independently at 18 months of age. Her speech was delayed and she had full sentences in first grade. She received special education with occupational therapy and adaptive physical education from two years of age until 4th grade and she was around one year behind her peers when she started Kindergarten. She also received resource classes for 1.5-2 hours per day at school. A developmental assessment at 10 years of age showed a verbal comprehension score of 87 (19th centile), perceptual reasoning score of 75 (<1st centile), working memory sore of 74 (4th centile) and a processing speed score of 56 (<1st centile). She has received diagnoses of mild to moderate intellectual disability although her verbal comprehension score was in the normal range as above, attention deficit hyperactivity disorder (ADHD) combined type, and developmental coordination disorder. She has had difficulties with mood regulation, anger management and anxiety that has been treated with methylphenidate. At 12 years of age, she was in 6th grade and had strengths in reading and writing. She tested at average and below average for the state standards. She was diagnosed with dyscalculia and had difficulty with focusing, telling the time and understanding money. A tight frenulum, narrow palate and difficulties with articulation were noted in early childhood and a tonsillectomy and adenoidectomy were performed for sleep apnea and snoring. She continues to have encopresis several times per week. She has not 4
had menstrual periods. In the family, her oldest brother showed signs of depression at 17 years of age and a maternal aunt was diagnosed with bipolar disorder. Ethnicity was European Caucasian for both parents and there was no known consanguinity. On examination, she was conversant with hesitant speech. Her height was 165 cm (92nd centile) and weight was 42.4 kg (41st centile). OFC was 54.2 cm (75-90th centile). She had a short columella, open mouth and a high arched palate. There was arachnodactyly of her thumbs, fingers and toes and right 3rd finger measured 8.5 cm (>97th centile). She had mild elbow contractures. She had mild hypotonia, but there were no other neurological signs. Patient 3 Patient 3 was a 5-year-old boy who was non-verbal. He was diagnosed with severe autism spectrum disorder following loss of words and regression between the ages of two and three years. He was born prematurely at 29.5 weeks of gestation and remained in the neonatal intensive care unit for six weeks. He was not dysmorphic and had normal growth parameters. He had a normal 24 hour electroencephalogram (EEG) that was performed due to concerns regarding regression. A brain MRI scan showed no structural malformations. Patient 4 Patient 4 was born at 30 weeks gestation to a 34 year old, G4P2Ab2 mother. Birthweight was 1,265 g (10-25th centile). He had unilateral, left-sided complete cleft lip and palate that was repaired without complications. A cranial ultrasound scan showed grade 1 intraventricular hemorrhage, but was otherwise normal. He remained in the neonatal intensive care unit for 41 days and was followed regularly in the high risk infants clinic after discharge. Developmental delays were noted in his second year of life and he was evaluated in genetics clinic at 3 years of age. He had a prominent forehead and flattening of the midface associated with his clefting, but his examination was otherwise normal. A karyotype and array comparative genomic hybridizarion were normal. He was admitted for suspected seizure like activity, but an EEG, including extended video monitoring, showed no epileptic pattern. He was last seen at four years of age. Growth parameters were in the normal range and his facial features were unchanged. Motor skills were normal, but he continued to have mild speech and language delays and was receiving speech therapy, physical therapy and occupational therapy. Patient 5 5
Patient 5 was a male who was delivered at 39 weeks gestation. Birthweight was 4,167 g (99th centile) and length was 53 cm (95th centile). Significant hypotonia was noted after birth and he was diagnosed with dilated cardiomyopathy. He had a Berlin ventricular assist device prior to transplant. During the time he had the Berlin, he developed a clot with emboli and subsequently suffered strokes. He had had seizures around the time of his strokes and was started on an anticonvulsant. He underwent heart transplantation at 3 months of age. Brain MRI at age 2 years revealed chronic infarctions in both cerebral hemispheres, including in the left parietal lobe, left temporal occipital region, and right frontal lobe. EEG at age 2 years was abnormal, but considered referable to the known history of bihemispheric stroke. He had hypotonia, hypermobility, and gross motor delay. He walked at 2.5 years and talked at 2 years. At 6 years of age he had to crawl up stairs, could not jump, was unable to pedal a tricycle, and had an atypical walk and run. The child has not had IQ testing, but he does carry a diagnosis of ADHD. At the time of diagnosis, he was in kindergarten and received physical therapy and occupational therapy. On physical exam, no dysmorphic features were noted. He had short stature, decreased muscle tone, joint hypermobility, pronation of the feet, and a wide-based gait. He had a chronic history of feeding difficulties and at age 6 was on nasojejunal feedings. Patient 6 Patient 6 was a female born at 38 weeks of gestation. Her mother reportedly suffered from epileptic seizures in early childhood, but was not treated with medications. The child had normal developmental milestones, with indepedent walking at 14 months of age and first words at 18 months of age. Her speech development was delayed and she received speech therapy and went to a mainstream kindergarden. At 4 years of age, she presented with nocturnal, generalized tonic-clonic seizures. An EEG showed centro-temporal epileptic discharges. Therapy with sulthiame was commenced but did not completely control the seizures. Patient 7 Patient 7 was a 2 year old female who presented with seizures at 4 months of age. She has been diagnosed with intractable epilepsy of unknown etiology. An EEG at 8 months of age showed non-specific left temporal slowing and multifocal epileptiform discharges. Electrographic seizures were recorded occasionally with clinical accompaniment and were characterized by generalized polyspike and wave activity followed by 6
generalized decrement. A follow up EEG at 13 months of age showed bitemporal slowing, bitemporal and bioccipital synchronous and independent epileptiform discharges. A brain MRI at 4 months of age showed no abnormalities. A follow up MRI at 21 months also showed no structural abnormalities. She has exhibited significant developmental delays. From a gross motor standpoint, she sat independently at 2.5 years of age. She cannot stand without support and was not taking independent steps. From a fine motor perspective, she could reach for objects and transfer them between her hands. She had developed a pincer grasp. From a speech and language standpoint, she had no words at 2.5 years of age. She had generalized hypotonia that was symmetrical. At two years of age, she began developing laughing spells and started biting her feet and toes and other people.
Materials and Methods Exome sequencing was performed with a trio approach on probands and both biological parents for all patients. All sequence variants are described with reference to JMJD1C transcripts NM_032776.2/ NM_001322252. Exome capture for Patient 1 was done using the SeqCap EZ Exome Probes v3.0 (Roche Sequencing, Pleasanton, USA). Exome libraries were sequenced on an Illumina HiSeq instrument (Illumina, San Diego, USA) with 151bp paired-end reads at a median coverage of 100x. Sequence reads were aligned to the hg19 reference genome using BWA Variants were subsequently called by the GATK unified genotyper, and annotated using a custom diagnostic annotation pipeline. A de novo approach was applied for candidate gene identification. For patients 2, 3, 4, 5 and 7 who underwent WES as a clinical test, sequencing technology and the variant interpretation protocol have been previously reported (Tanaka et al., 2015). Bi-directional sequence reads were assembled and aligned to reference sequences based on NCBI RefSeq transcripts and human genome build GRCh37/UCSC hg19. Using a custom-developed analysis tool (XomeAnalyzer), data were filtered and analyzed to identify sequence variants and most deletions and duplications involving three or more coding exons (Retterer et al., 2015). Reported clinically significant variants were confirmed by an appropriate orthogonal method in the proband. Sequence and copy number variants were reported according to the Human Genome Variation Society (HGVS) or International System for Human Cytogenetic Nomenclature (ISCN) 7
guidelines, respectively. Reportable variants include pathogenic variants, likely pathogenic variants and variants of uncertain significance. Likely benign and benign variants, if present, were not routinely reported. For Patient 6, WES was performed as a trio with her biological parents at the Institute of Clinical Molecular Biology at the University of Kiel and the Cologne Center for Genenomics (https://varbank.ccg.uni-koeln.de) using the Nextera Rapid Capture Expanded Exome Kit and the Illumina HiSeq2500. The data were analyzed with a standardized pipeline as reported previously (Helbig et al., 2019).
Results A summary of the clinical features of these seven patients is provided in Table 1. The variants in JMJD1C are shown in Table 2 and are not redescribed in the text. In Patient 2, a heterozygous, de novo variant, c.833delC, predicted to result in p.(Pro278Leufs*102), was also identified in the SRCAP gene. This variant has not been seen in public databases and was also predicted to be pathogenic by the reporting laboratory. Nonsense or frameshift variants that result in the formation of a C-terminal-truncated SRCAP protein miss critical functional domains and act as dominant negative mutations that cause Floating Harbor syndrome (Messina et al., 2016). However, this patient did not have short stature or the facial differences that are typically found in children with FHS. Patient 4 also had a missense variant in CACNA1A, c.5666A>G, predicting p.(Asn1889Ser) that was paternally inherited and classified as a variant of unknown significance. Patient 5 had a second, likely pathogenic variant that was identified in TTN, c.62426-2A>C, that was maternally inherited. This TTN variant is believed to be the cause for the child’s cardiomyopathy and may be contributing to the hypotonia. Patient 6 carried an additional, heterozygous de novo variant in WDR59, c.896A>G, predicting p.(Asp299Gly), that could also be relevant to the seizures and speech delay. Lastly, Patient 7 had 2% heteroplasmy for the m.10197G>A variant, predicting p.(Ala47Thr) in the MT-ND3 gene that was predicted to probably damaging with MutationTaster (p = 0.999). However, the degree of heteroplasmy was considered to be to low to account for the patient’s neurocognitive status.
Discussion 8
Herein we report seven patients with de novo, heterozygous variants in JMJD1C, comprising three missense variants [c.5072A>G, predicting p.(Asn1691Ser), c.1100T>C, predicting p.(Leu367Pro) and c.349G>A, predicting p.(Val117Ile)], two frameshift variants [c.1082_1098del17, predicting p.(Lys361Thrfs*4) and c.326_326delC, predicting p.(Pro109Leufs*3)], mosaicism for a frameshift variant [c.3167_3207del41, predicting p.(Ser1056Cysfs*10)] and mosaicism for an intronic variant [c.5863-6T>G], that was predicted to disrupt splicing. All patients shared neurocognitive phenotypes with developmental delays. Three patients had attention deficit disorders, two had autism spectrum disorder and two patients suffered from seizures. There were no complications in pregnancy or at the birth. Growth parameters were normal and dysmorphic features were mild or absent. There was no individual with a Rett syndrome-like phenotype or autism spectrum disorder as previously described (Neale et al., 2012; Iossifov et al., 2014; Sáez et al., 2016) and all of the patients appeared to have non-specific, neurocognitive differences. All of the variants in JMJD1C were shown to be de novo, with the exception of Patient 7, in whom parents were unavailable for testing. The de novo nature of the variant with confirmed paternity and maternity from exome sequencing constitutes strong evidence for pathogenicity (PS2; Richards et al., 2015). In addition, all of the variants were absent from control databases that constitutes moderate evidence for pathogenicity (PM2; Richards et al., 2015) except for the missense variants in Patient 5. All of the variants were predicted to be disease causing by MutationTaster (Schwarz et al., 2014) and the missense variants were highly conserved (Table 2) with the exception of the variaint in Patient 1, consistent with the criteria for multiple lines of computational evidence that support a deleterious effect on the gene/gene product that constitutes supportive evidence for pathogenicity (PP3; Richards et al., 2015). Patient 3 had mosaicism for a de novo, intronic variant in JMJD1C, c.5863-6T>G in intron 15. This variant was predicted to alter the wildtype donor site to most probably affect splicing (Human Splicing Finder), although variants affecting the same splice site, c.5863-3T>C and c.5863-4G>A, have been found in 12/275676 and 4/244,612 individuals in gnomAD. JMJD1C is under strong constraint for loss of function variants, with 107.7 such variants predicted and only 3 observed (pLI = 1.0; gnomAD). It is possible that the loss of function variants will prove to be more pathogenic than missense variants in this gene, but there are too few patients for analysis at present. Although 9
JMJD1C variants have previously been associated with intellectual disability in some of the patients presented in this report, genetic factors in addition to the the JMJD1C variant may be important in the pathogenesis of the neurocognitive phenotype. Two patients had additional variants in genes known to be associated with intellectual disabililty, including SRCAP (Messina et al., 2016) and CACNA1A (Reinson et al., 2016). Somatic mosaicism was present for two variants (Table 2). For two patients, the nucleotide substitution has been found as a heterozygous variant in gnomAD (Table 2). One of the patients also had a likely pathogenic variant in TTN, a gene associated with cardiomyopathy and/or skeletal muscle myopathy and another had a variant in WDR59 that was considered a more likely explanation of the phenotype. The last patient was heteroplasmic for a pathogenic mitochondrial variant. JMJD1C was first studied as TRIP8, a member of the TRIP1 to TRIP15 family of genes that encode thyroid hormone receptor beta (TR beta)-binding proteins (Katoh and Katoh, 2003). The gene has 26 exons that encode a 2,540 amino acid protein with two bipartite nuclear localization signals (codons 352-368 and 2,3652,381), a TRI8H1 domain (codon 1,697-1,873), TRI8H2 domain (codon 2,057-2,351) and a JMJC domain (codon 2,387-2,486; Katoh and Katoh, 2003). As JMJC domain proteins are implicated in chromatin remodeling, TRIP8 was predicted to be a transcriptional regulator associated with nuclear hormone receptors (Katoh and Katoh, 2003). TRIP8 interacts with T3 receptor β in a T3-dependent manner, but could also interact with the retinoid X receptor (RXR) and other transcription factors, including the vitamin D receptor, peroxisome proliferation-activated receptor (PPAR)-α and PPAR-γ and retinoic acid receptor (RAR)-α (Lee et al., 1995; Yuan et al., 1998). The first report of disruption of the JMJD1C gene in association with a phenotype concerned a nine-year old male who was evaluated for impairment in social and communication skills (Castermans et al., 2007). His milestones were normal, but early language and social development were delayed and he did not develop fantasy or pretend play and did not socialize with his peers. An assessment showed deficits in social reciprocity, impairment of non-verbal communication, mild delays in expressive and receptive language and marked impairment in social perspective taking. He fulfilled the DSM-IV criteria for the diagnosis of highfunctioning autistic spectrum disorder despite a normal intelligence quotient (Castermans et al., 2007). This 10
child carried a de novo, balanced paracentric inversion [46,XY,inv(10)(q11.1;q21.3)], in which the distal breakpoint interrupted the first intron of JMJD1C and was predicted to disrupt both the TRIP8a and TRIP8b transcripts, with possible preservation of an alternative TRIP8c transcript (Castermans et al., 2007). Subsequent large-scale sequencing studies on children with autism spectrum disorders revealed additional heterozygous, de novo variants in JMJD1C. In a study performing trio exome sequencing on patients with autism spectrum disorder, one missense variant, p.(Val1070Ile), and one nonsense variant, p.(Arg69*) in were identified (Neale et al., 2012; Iossifov et al., 2014). Another study examined 215 patients presenting with autism spectrum disorder, intellectual disability and Rett syndrome without known genetic defects and detected seven nucleotide variants clustering in exon 10 of JMJD1C that were not present in control databases (Sáez et al., 2016). Two of these variants were considered to be pathogenic, including a heterozygous, de novo variant, c.488C>T, predicting p.(Pro163Leu), in a 29 year old female who was diagnosed with classical Rett syndrome (Sáez et al., 2016). This patient demonstrated loss of social interaction at 18 months of age and additional findings of delayed speech development, gait dyspraxia, hand-washing stereotype, teeth grinding, air swallowing, kyphoscoliosis and tonic epilepsy (Sáez et al., 2016). Although endogenous JMJD1C is present in the cytoplasm, mutant p.(Pro163Leu)-JMJD1C was markedly enriched in nuclear chromatin and was less efficient in demethylating MDC1, a non-histone target of JMJD1C, compared to wildtype JMJD1C (Sáez et al., 2016). In addition, an immunoprecipitation assay demonstrated an interaction between JMJD1C and MECP2, with less efficient binding of the JMJD1C-Pro163Leu mutant protein compared to wildtype JMJD1C, thus potentially explaining the phenotypic overlap between the patient’s phenotype and Rett syndrome (Sáez et al., 2016). Another heterozygous, de novo variant in JMJD1C, c. 3559A>G, predicting p.(Thr1187Ala) was also noted in a male patient with intellectual disability, but was not functionally studied. Deletions including JMJD1C have also been published. A three year old Japanese female who was unable to sit or to crawl and had no single words reported to have a 10.4 Mb deletion at chromosome 10q21.3q22 that spanned 84 RefSeq genes, including CTNNA3 and JMJD1C (Shimojima et al., 2017). This child had Tetralogy of Fallot, hypotonia, growth delays and dysmorphic features comprising hypertelorism, 11
downslanting palpebral fissures, epicanthal folds, a flat nasal bridge, low-set ears and a low hairline with a webbed neck and small hands and feet (Shimojima et al., 2017). However, although haploinsufficiency for JMJD1C was considered as a possible explanation for the phenotype, numerous other genes were also deleted. JMJD1C has also been suggested to be a modifier gene for congenital heart disease (Guo et al., 2015), as sequencing 184 individuals with 22q11.2 deletion syndrome for modifying genetic variants revealed ten rare single nucleotide variants in JMJD1C in nine patients with congenital heart disease that were not present in controls (Guo et al., 2015). However, none of these patients reported here demonstrated cardiac defects.
Conclusion We present seven patients with heterozygous variants in JMJD1C and neurocognitive differences that included learning delays, ADHD, autism spectrum disorder and seizures. There were no other consistent clinical findings. All patients had either mosaicism, a second variant that could be influencing the intellectual disability, or a variant that was found in the heterozygous state in a public database. In the literature, only one JMJD1C variant has undergone functional evaluation. We conclude that further data strengthening the association of JMJD1C variants with neurocognitive deficits is needed. Further reports of patients, functional studies or animal models are still required for a more definitive implication of JMJD1C in the pathogenesis of intellectual disability.
12
Acknowledgements We are grateful to the patients and families for their participation.
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Table 1. Clinical features of patients with JMJD1C variants Patient 1 2 Sex/Age at reporting M/11 y 11 m F/12 y Gestation 40 w 39 w Birth parameters th Weight 3,750g (50-75 ) 3,005g (10-25th) Length 56 cm (>97th) NA Neonatal period Gastroesophageal reflux
Development Age at walking Age at first words Neurocognitive Developmental delays ADD/ADHDa Autism Seizures Hypotonia Growth parameters Height Weight Head circumference Dysmorphic features Prominent forehead Flat midface Short columella Open mouth Narrow palate Musculoskeletal Arachnodactyly Elbow contractures Other Strabismus Investigations MRIb brain c
EEG
2y 2.5 y
18 m 6y
+ +
+ + -
3 M/5 y 29.5 w
4 M/4 y 30 w
5 M/6 y 39 w
6 F/4 y 38 w
7 F/2 y 36 w
NA NA
1,265g (10-25th) NA Left cleft lip/palate Intraventricular hemorrhage
4,167g (90-97th) 53 cm Dilated cardiomyopathy; strokes secondary to treatment; seizures secondary to strokes
NA NA
2,400g (10-25th)
NA NA
NA NA
2.5 y 2y
14 m 18 m
-
+
+ + -
+
+ 158 cm (+0.42 SD) 37 kg (-1.8 SD) 55 cm (+0.53 SD)
165 cm (92nd) 42.4 kg (41st) 54.2 cm (75-90th)
+ +
+ +
NA NA NA
80.5 cm (3rd) 10.1 kg (2nd) NA
+ NA NA NA
NA NA NA
103 cm (0.2nd) 21.6 kg (50th) 51.4 cm (46th)
NA
+ +
+
+ + + + + + Not done
Not done
Normal
Not done
Not done
Not done
Normal
Normal
Infarctions (due to Berlin heart), Abnormal (secondary to bihemispheric stroke)
Not done
Normal
Epileptic discharges
Epileptic discharges
Y = years; m = months; w = weeks; NA = not available. ADD/ADHDa = attention deficit hyperactivity disorder; MRIb = magnetic resonance imaging; EEGc = electroencephalogram.
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Table 2. Sequence variants in JMJD1C gene in patients with developmental delays Gene Nucleotide Amino acid ZygosInheritMosaicism Alteration Alteration ity ance
PolyPhen2
Mutation Tas-ter
ExAC browser/ 1000 genomes
gnomAD
ConserVation*
Patient 1 JMJD1C; c.5072A>G p.(Asn1691Ser) Het. de novo B; 0 DC; 1/30,978; Pt, Mm, Gg, Xt NM_001322252.1 p=1 3.228e-5 Patient 2 JMJD1C; c.3167_3207 p.(Ser1056Cysfs*10) Het. de novo Y NA DC; NA NM_001322252.1 del41 p=1 Patient 3 JMJD1C; c.5863NA Het. de novo Y NA DC; NA NM_001322252.1 6T>G p=1 Patient 4 JMJD1C; c.1082_1098 p.(Lys361Thrfs*4) Het. de novo NA DC; NA NM_001322252.1 del17 p=1 Patient 5 JMJD1C; c.1100T>C p.(Leu367Pro) Het. de novo PD; 0.983 DC; p = 3/267030; Pt, Mm, Mmus, NM_032776.2 0.999 1.123e-5 Gg, Dr, Xt Patient 6 JMJD1C c.349G>A p.(Val117Ile) Het. de novo B; 0.012 DC; p = Pt, Mm, Mmus, NM_032776.2 0.983 Gg, Dr Patient 7 JMJD1C c.326delC p.(Pro109Leufs*3) Het. Not NA DC; p = 1 Pt, Mm, Mmus, NM_032776.2 known Gg, Dr Conservation* = amino acid residue conservation in different species as determined from MutationTaster: Pt = Pan troglodytes; Mm = Macacca mulatta; Mmus = Mus musculus; Gg = Gallus gallus; Tr =Takifugu rubripes; Dr = Dario rerio; Xt = Xenopus tropicalis. Het. = heterozygosity; B = benign; DC = disease causing; NA = not applicable; PD = probably damaging.
15
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Anne Slavotinek: Conceptualization, Resources, Writing – original draft, Writing – review and editing. Johanna M van Hagen: Resources, Writing – original draft, Writing – review and editing. Louisa Kalsner: Resources, Writing – original draft, Writing – review and editing. Shashidhar Pai: Resources, Writing – original draft, Writing – review and editing. Laura Davis-Keppen: Resources, Writing – original draft, Writing – review and editing. Lisa Ohden: Resources, Writing – original draft, Writing – review and editing. Yvonne G. Weber: Resources, Writing – original draft, Writing – review and editing. Erica L. Macke: Resources, Writing – original draft, Writing – review and editing. Eric W. Klee: Resources. Eva Morava: Resources. Lauren Gunderson: Resources. Richard Person: Investigation. Shuxi Liu: Investigation. Marjan Weiss: Resources, Writing – original draft, Writing – review and editing.