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Regulatory Mutations of FOXG1 in the Context of Topological Domains
Abstracts been associated with neurodevelopmental disorder (NDD) due to dysregulation of a network of neuronal target genes, including Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25. A heterozygous missense mutation in ZBTB20 was also recently described as the cause of Primrose syndrome (PRIMS, OMIM # 259050). Additionally, ZBTB20 resides within the critical region of the wellestablished 3q13.31 microdeletion syndrome (OMIM #615433). However, a syndrome caused by sole disruption of ZBTB20 has not been reported yet. Here, we report an eleven year-old Caucasian adopted male referred for developmental delay (DD), attention-deficit hyperactivity disorders (ADHD), dysmorphic facies, speech impairment, short stature, dental overcrowding, brachydactyly of the feet, and joint hypermobility. A SNP-chromosomal microarray analysis revealed a 747 kb heterozygous loss of 3q13.31 arr[hg19] 3q13.31(114,044,159–114,791,147)x1, which includes exons 2–9 of the ZBTB20 protein, NM_015642.5. This is a dosage sensitive gene with a haploinsufficency index of 0.19%. This loss partially overlaps (43%) with rare copy number loss in the databases of genomic variants present in 0.0000824 % (4/48531 controls). The smallest region of overlapping in the 3q13.31 microdeletion syndrome harbors 5 RefSeq genes: DRD3 (a dopamine receptor), ZNF80, TIGIT, MIR568 and ZBTB20 (exons 7-10, NM_015642.5). This syndrome is characterized by marked global DD, speech delay, intellectual disability, autism spectrum disorder (ASD), ADHD, seizures, brain malformations, characteristic face with a short philtrum and protruding lips, and abnormal male genitalia, some of which are also present in our case. Patients with PRIMS exhibit features overlapping those of the chromosome 3q13.31 deletion syndrome, but also have ossified ear cartilage, severe muscle wasting, bony changes (joint contractures -fingers, hips, knees-, generalized osteoporosis), and abnormalities of glucose metabolism. All of these features are absent in our patient. To date, four cases have been reported with truncation of ZBTB20 by a translocation, inversion and partial (1.3 Mb) deletion [Rasmussen, et al 2014], and another microdeletion (392 kb, DECIPHER ID 28412), disrupting the gene at different breakpoints, from intron 1 to exon 7. All patients share a similar phenotype with our case. The significant difference between these five patients and those with a 3q13.31 microdeletion is the lack of seizures, which are attributed to deletion of DRD3 in cases with the 3q13.31 microdeletion. Our report provides further evidence that dosage imbalance of ZBTB20 results in a phenotype. Our patient is the second report with an intragenic deletion of ZBTB20. Collection of additional cases with a similar microdeletion will aid further delineation of the common and rare features associated with disruption of ZBTB20; which possibly represents a new pathogenic copy number variant.
245 scriptional Start Sites (TSS), housekeeping genes, binding sites for CTCF insulator factor and SINE elements (1). Different structural variations like deletions and translocations may interfere with the TAD organization. Translocations with breakpoints outside of TAD boundaries (the majority) will invariably interfere with TAD organization, creating fusion domains, whereas deletions may or may not, depending on position and size. Although the majority of TADs are identical in human embryonic cells (hESC) and IMR90 fibroblast, some loci display a differential pattern in the two cell lines. This is exemplified by the Forkhead box G1 (FOXG1) gene on 14q12, located within a 2 Mb sized TAD in IMR90 cells which is split into two TADs in hESC. FOXG1 encodes a winged-helix transcriptional repressor critical for early telencephalon development. Coding mutations of FOXG1 causes a congenital variant of the severe neurodevelopmental disorder Rett syndrome2. Balanced chromosomal rearrangements with breakpoints downstream of FOXG1 have been shown to cause the same phenotype as coding mutations (2,3). Such long range position effects (LRPE) are presumably caused by the removal of cis-acting regulatory elements. The LRPE critical region at the FOXG1 locus is not defined, and intra-TAD deletions that remove the hESC-specific TAD boundary distal to FOXG1 have been suggested to exemplify enhancer adoption (4), with the establishment of new deleterious enhancer-target gene interactions (5). Herein we have mapped two new LRPE-associated translocations by mate-pair sequencing, which we use together with additional microdeletions distal to FOXG1 to define the critical LRPE-region and the evidence for or against enhancer adoption as a major feature of the FOXG1-locus.
References 1. Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012;485:376–380. 2. Alosi D, Klitten LL, Bak M, et al. Dysregulation of FOXG1 by ring chromosome 14. Mol Cytogenet 2015;8:24. 3. Shoichet SA, Kunde SA, Viertel P, et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation and microcephaly. Hum Genet 2005;117:536–544. 4. Lettice LA, Daniels S, Sweeney E, et al. Enhancer-adoption as a mechanism of human developmental disease. Hum Mutat 2011;32:1492–1499. 5. Ibn-Salem J, Köhler S, Love MI, et al. Deletions of chromosomal regulatory boundaries are associated with congenital disease. Genome Biol 2014;15:423.
51 Triploidy in a Live-Born Female With Normal NonInvasive Prenatal Testing Results Ferrin C. Wheeler, Maria Gilliam-Krakauer
50 Regulatory Mutations of FOXG1 in the Context of Topological Domains Mana M. Mehrjouy, Ana Carolina Fonseca, Nadja Ehmke, Busa Tiffany, Maria Antonietta Mencarelli, Antonio Novelli, Mads Bak, Niels Tommerup
Recent HiC proximity mapping have revealed a 3D-organization of the human genome where cis-regulatory interactions occur within megabase-sized topological associating domains (TADs) (1). TADs are separated by boundaries (TDB) which are enriched in Tran-
Non-invasive prenatal testing (NIPT) has become an increasingly popular option for pregnancies with abnormal ultrasound (U/S) findings. Although it has high clinical sensitivity and specificity for trisomy 21, some other, rarer cytogenetic conditions are less likely to be detected with certain NIPT methods. Triploidy is a rare genetic condition that usually results in miscarriage or stillbirth. Very few triploid pregnancies result in a live birth. We present a case of a female neonate with multiple anomalies and normal non-invasive testing who was diagnosed with dygynic triploidy after birth. Fetal U/S at 19 weeks was abnormal for a
245 scriptional Start Sites (TSS), housekeeping genes, binding sites for CTCF insulator factor and SINE elements (1). Different structural variations like deletions and translocations may interfere with the TAD organization. Translocations with breakpoints outside of TAD boundaries (the majority) will invariably interfere with TAD organization, creating fusion domains, whereas deletions may or may not, depending on position and size. Although the majority of TADs are identical in human embryonic cells (hESC) and IMR90 fibroblast, some loci display a differential pattern in the two cell lines. This is exemplified by the Forkhead box G1 (FOXG1) gene on 14q12, located within a 2 Mb sized TAD in IMR90 cells which is split into two TADs in hESC. FOXG1 encodes a winged-helix transcriptional repressor critical for early telencephalon development. Coding mutations of FOXG1 causes a congenital variant of the severe neurodevelopmental disorder Rett syndrome2. Balanced chromosomal rearrangements with breakpoints downstream of FOXG1 have been shown to cause the same phenotype as coding mutations (2,3). Such long range position effects (LRPE) are presumably caused by the removal of cis-acting regulatory elements. The LRPE critical region at the FOXG1 locus is not defined, and intra-TAD deletions that remove the hESC-specific TAD boundary distal to FOXG1 have been suggested to exemplify enhancer adoption (4), with the establishment of new deleterious enhancer-target gene interactions (5). Herein we have mapped two new LRPE-associated translocations by mate-pair sequencing, which we use together with additional microdeletions distal to FOXG1 to define the critical LRPE-region and the evidence for or against enhancer adoption as a major feature of the FOXG1-locus.
References 1. Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012;485:376–380. 2. Alosi D, Klitten LL, Bak M, et al. Dysregulation of FOXG1 by ring chromosome 14. Mol Cytogenet 2015;8:24. 3. Shoichet SA, Kunde SA, Viertel P, et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation and microcephaly. Hum Genet 2005;117:536–544. 4. Lettice LA, Daniels S, Sweeney E, et al. Enhancer-adoption as a mechanism of human developmental disease. Hum Mutat 2011;32:1492–1499. 5. Ibn-Salem J, Köhler S, Love MI, et al. Deletions of chromosomal regulatory boundaries are associated with congenital disease. Genome Biol 2014;15:423.
51 Triploidy in a Live-Born Female With Normal NonInvasive Prenatal Testing Results Ferrin C. Wheeler, Maria Gilliam-Krakauer
50 Regulatory Mutations of FOXG1 in the Context of Topological Domains Mana M. Mehrjouy, Ana Carolina Fonseca, Nadja Ehmke, Busa Tiffany, Maria Antonietta Mencarelli, Antonio Novelli, Mads Bak, Niels Tommerup
Recent HiC proximity mapping have revealed a 3D-organization of the human genome where cis-regulatory interactions occur within megabase-sized topological associating domains (TADs) (1). TADs are separated by boundaries (TDB) which are enriched in Tran-
Non-invasive prenatal testing (NIPT) has become an increasingly popular option for pregnancies with abnormal ultrasound (U/S) findings. Although it has high clinical sensitivity and specificity for trisomy 21, some other, rarer cytogenetic conditions are less likely to be detected with certain NIPT methods. Triploidy is a rare genetic condition that usually results in miscarriage or stillbirth. Very few triploid pregnancies result in a live birth. We present a case of a female neonate with multiple anomalies and normal non-invasive testing who was diagnosed with dygynic triploidy after birth. Fetal U/S at 19 weeks was abnormal for a