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Maternally inherited autosomal dominant intellectual disability caused by 16p13.3 microduplication
European Journal of Medical Genetics 59 (2016) 210e214
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
Maternally inherited autosomal dominant intellectual disability caused by 16p13.3 microduplication Cha Gon Lee a, *, Eunhae Cho b, Young Min Ahn a a b
Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Republic of Korea Green Cross Genome, Yongin, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 October 2015 Received in revised form 4 February 2016 Accepted 6 February 2016 Available online 9 February 2016
A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of RubinsteineTaybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a 1 Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient's mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 16p13.3 duplication syndrome Maternal inheritance Autosomal dominant Intellectual disability CREBBP
1. Introduction
2. Clinical data
A 16p13.3 duplication syndrome has been recently suggested as a novel recognizable syndrome as a reciprocal microduplication disease of RubinsteineTaybi syndrome (Thienpont et al., 2010). To date, only about 25 cases have been reported (Chen et al., 2012; Dallapiccola et al., 2009; Demeer et al., 2013; Friedman et al., 2006; Li et al., 2013; Marangi et al., 2008; Mattina et al., 2012; Thienpont et al., 2007, 2010; Tuysuz et al., 2012). This duplication involves the RubinsteineTaybi critical region and includes the CREBBP (cyclic adenosine monophosphate [cAMP]eresponse element-binding protein [CREB]-binding protein) gene. Clinical features include mild-to-moderate developmental delay, normal growth, characteristic facial features, mild arthrogryposis with camptodactyly and proximally implanted small thumb. Most duplications have been reported de novo (Thienpont et al., 2010). Here, we describe a boy and his mother with an approximately 1 Mb-sized duplication of 16p13.3, identified by single nucleotide polymorphism (SNP) array testing. He and his mother both displayed intellectual disability.
2.1. Patient
* Corresponding author. Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711, Republic of Korea E-mail address: [email protected] (C.G. Lee). http://dx.doi.org/10.1016/j.ejmg.2016.02.005 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
An 11-year-old boy visited the pediatric neurology clinic of Eulji General Hospital with maternally inherited intellectual disability on December 30, 2014. He was born vaginally after 37 and 1/7th weeks of gestation, weighing 2500 g (10e25th percentile), length of 43 cm (10e25th percentile), and an occipitofrontal circumference of 33 cm (25e50th percentile) from non-consanguineous Korean parents. His mother and father were 26 and 39 years of age, respectively (Fig. 1A). Except for the mother, the family had no history of neurologic disease or developmental delay. No feeding difficulties or hypotonia occurred during early infancy. He had received frequent admissions and treatments for respiratory, gastrointestinal, and upper urinary tract infections during infancy. He had global mild developmental delay, but did not show psychiatric, sleep, and behavior problems. In a physical examination at 11-years-of-age, he showed normal growth, with a body weight of 38.1 kg (0.19, standard deviation score, SDS), height of 151.3 cm (0.96 SDS), body mass index (BMI) of 16.64 kg/m2 (0.81 SDS), and head circumference of 50 cm (0.87 SDS). He had upslanted palpebral fissure, mild ptosis and low-set ears (Fig. 1B and C). Extremities were featureless (Fig. 1D and E). Other neurological examinations were normal. His first
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Fig. 1. Pedigree and photographs. (A) Pedigree of the family with maternal inherited intellectual disability. The black arrow indicates the proband. Darkened symbols represent affected members. Stars indicate sampled subjects. (BeC) Patient facial photographs at 11-years-of-age show the up-slanted palpebral fissure, ptosis and low-set ears. (D) Photograph of the patient's hands, illustrating absence of arthrogyposis-like features in both hands. (E) The skeletal bone age of the left wrist corresponds to according to the Greulich and Pyle standard at 11-years-of-age, which was suitable for his chronological age. (F) He had only cave of septum pellucidum without definite brain anomalies on 1.5 T magnetic resonance imaging. (GeH) The mother showed mild mid-face hypoplasia, round nose tip, and low-set ears. (I) She had mild flexion deformities of the proximal interphalangeal joints and proximally implanted small thumb with shorter distal phalanges in both hands.
neurodevelopmental evaluation was checked at 11-years-of-age. Intellectual functioning was measured by the Korean Wechsler Intelligence Scale for Children fourth edition (K-WISC-IV). He had moderate intellectual disability with Full Scale IQ (FSIQ) 49, verbal comprehension index (VCI) 47, perceptual reasoning index (PRI) 47, working memory index (WMI) 50, and processing speed index (PSI) 74. His social maturation quotient (SQ 52.73) and social age (SA) of 5.80 years also indicated moderate trainable intellectual disability. The Bender Gestalt test result was suggestive of motor incoordination and brain dysfunction. Laboratory tests including complete blood count, chemistry, electrolytes, and pituitary function test were within normal range. The results of an immunology blood test performed due to frequent infectious disease were nonspecific. Brain magnetic resonance imaging was normal, except for the cave of septum pellucidum (Fig. 1F). Voiding cystourethrogram revealed only a small diverticulum in the urinary bladder. 2.2. Patient's mother When the patient's mother first visited our clinic with her son, she was 38-years-old. She was the second child of healthy nonconsanguineous Korean parents. She had one healthy elder sister. There was no family history of neurologic disease or developmental delay except for her son. She had graduated high school and
married at 23-years-of-age. A physical examination showed a body weight of 54.5 kg (0.07 SD), height of 160.1 cm (0.13 SD), and body mass index of 21.26 kg/ m2 (0.05 SD). She had a dull facial expression and displayed characteristic facial features including mild mid face hypoplasia, round nose tip and low set ear (Fig. 1G and H). In our clinic, she was shy and quiet. She had camptodactyly and a proximally implanted small thumb with shorter distal phalanges in both hands (Fig. 1I). When evaluated at 26-years-of-age, she revealed a mild level of intellectual disability by the Korean Wechsler Adult Intelligence Scale (K-WAIS); FSIQ 59, VIQ 63, and PIQ 58. The clinical characteristics of the patient and his mother are summarized in Table 1. 3. Results 3.1. Patient Karyotyping, fluorescence in situ hybridization (FISH) for 22q11.2 and CGG repeat expansion analysis for FMR1 gene were all normal. Microarray analysis was carried out using the CytoScan 750 K high-resolution genotyping SNP microarray (Affymetrix, Santa Clara, CA, USA). Based on the human reference genome 37(NCBI37hg19) of the National Center for Biotechnology, the SNP assay revealed a region of gain spanning 1 Mb on chromosome 16p13.3 (Fig. 2B). The minimum start and stop point for this
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Table 1 Clinical characteristics of the patient, compared with reported common features of dup16p13.3. Trait
Proband
Mother
Previous reports (n ¼ 25)
Gender Inheritance Duplication size Small for gestational age Postnatal failure to thrive Intellectual disability (mild:moderated:severe) Behavioral problems Microcephaly/Macrocephaly Facial abnormalities Ptosis Blepharophimosis Upslanted palpebral fissure Bifid uvula: Cleft palate Low-set ears: Protruting ear: Dysplastic ears Midface hypoplasia: Bullbous nose tip Hand abnormalities Proximally implanted small thumb Camptodactyly Short finger Structural brain anomaly Structural cardiovascular anomalies
Male maternal 1025e1058 Kb none none moderate (K-WISC-IV, FSIQ 49) none none
Female ND 992Kbe1,059 Mb none none mild (K-WAIS-III, FSIQ 59) none none
M (17), F (8) de novo (22), inherited (2), ND (1) 375Kbe6.5 Mb 5/22 5/25 21/23 (5:15:1) 9/19 3/22 (3:0)
ptosis none upslanted palpebral fissure none low-set ears none
none none none none low-set ears mild midface hypoplasia, round nose tip
none none none cave of septum pellucidum none
proximally implanted small thumbs camptodactyly shorter distal phalanges ND ND
11/25 16/25 16/25 8/25 (2:5) 18/25 (10:7:9) 18/25 (15:7) 13/25 14/23 14/23 5/25 6/12 7/19 (ASD 4, VSD 2, TOF 1, dextrocardia1)
ND: no data available; K-WISC-IV; Korean Wechsler Intelligence Scale for Children fourth edition, KeWISCeIII: Korean Wechsler Adult Intelligence Scale third edition, FSIQ: full-scale intelligence quotient, ASD; atrial septal defect, TOF; tetralogy of Fallot.
duplication was estimated at 2,929,908 and 3,955,374, respectively, and the maximum breakpoint at 2,911,136 and 3,969,510, respectively. The size was estimated at 1025e1058 Kb and this region contained 23 OMIM genes and 31 RefSeq genes including CREBBP [NM 004380, MIN 600140]. The clinical and cytogenetic data was reported as case ID 5210 in the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) public database (www.ecaruca.net) (Feenstra et al., 2006). 3.2. Patient's parents G-banding analysis of the father and mother was achieved at a resolution above 550 bands. The results were normal, being 46,XY and 46,XX, respectively. SNP microarray analysis of the mother revealed a region of gain spanning about 992e1059 Kb on chromosome 16 with estimated minimum start and stop point for this gain at 2,963,260 and 3,955,374, respectively, and maximum breakpoint at 2,910,304 and 3,969,510, respectively (Fig. 2C). This region of gain contained 23 OMIM genes and 30 RefSeq genes. The gene list was the same as the patient's, except for the FLYWCH2 [NM 001142499] gene located on the starting breakpoint boundary. The difference of starting breakpoint between the patient and his mother was due to the SNP array probes. Probes are arrayed across the genome and signal intensity is used to identify regions that vary in copy number from what is expected. The density of probes at a given locus will determine resolution and therefore the extent of uncertainty. Because DNA between probes is not assayed by probebased experiments, there is no way to capture the precise location of variant boundaries. This necessarily results in fuzzy starting endpoints. The data of patient's mother was also submitted in the aforementioned public database as ECARUCA case ID 5211. 4. Discussion Many genetic conditions are related to changes in particular genes on chromosome 16 (Gilbert, 1999). The p13.3 regions on chromosome 16 are about 8 Mbp and harbor 107 genes (Martin et al., 2004). This region harbors chromosome 16p13.3 deletion syndrome, also known as RubinsteineTaybi syndrome (Roelfsema and Peters, 2007). The 16p13.3 duplication syndrome has recently
been recognized as a microduplication syndrome that is reciprocal to RubinsteineTaybi syndrome (Thienpont et al., 2010). The CREBBP gene is believed to represent the dosage sensitive critical gene responsible for these reciprocal duplication and deletion syndrome (Mattina et al., 2012; Roelfsema and Peters, 2007). The patient and his mother both had the approximate 1 Mb duplication on chromosome 16p13.3 (Fig. 2). These regions contained dosage changes of 23 common OMIM genes, included the well-known dosage sensitive CREBBP gene [NM 004380, MIN 600140] and several possible morbid genes, such as DNASE1 [NM 005223, MIM 152700], SLX4 [NM 032444, MIM 125505], MEFV [NM 000243, MIM 608107], and THOC6 [NM 024339, MIM 615403]. Known clinical features include normal growth, mild-to-moderate developmental delay, small and proximally implanted thumbs, mild arthrogryposis with camptodactyly, and dysmorphic facial features (ptosis, narrow palpebral fissures, up-slanted palpebral fissure, mid face hypoplasia, bullous nose tip) and are occasionally associated with heart defects, submucous cleft palate anomalies, and eye anomalies (strabismus, blepharophimosis, and ptosis) (Demeer et al., 2013; Li et al., 2013; Mattina et al., 2012; Thienpont et al., 2010; Tuysuz et al., 2012). The 23 genes were all candidate disease-causing genes responsible for the phenotype of our patient. In all patients reported so far, the smallest region of overlap contained only the CREBBP gene (Mattina et al., 2012). The actual gene that is the major dosage sensitive gene in 16p13.3 duplication syndrome is CREBBP. However, the dosage change of additional genes in this region probably accounts for the variable clinical features of this syndrome. In the present case, the patient and the mother showed normal growth and mild-to-moderate intellectual disability. Mild ptosis/upslanted palperbral fissure were apparent in the patient and mid-face hypoplasia, bulbous nose tip, camptodactyly/proximally implanted small thumb/shorter distal phalanges in his mother. Thus, the patient and his mother shared intellectual disability and low-set ears as common features (Table 1). The penetrance of this duplication seems variable, since two cases with inherited transmission involved normal carrier parents. Nevertheless, since most reported duplications arose de novo, there does appear to be a strongly reduced reproductive fitness associated with this genotype (Thienpont et al., 2010). A couple planning
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Fig. 2. Schematic diagram and SNP array results. (A) Diagrams amplified the common breakpoints regions on chromosome 16p13.3 (from 992 Kb to 1058 Kb) and showed the common genes of patient and his mother. (B) The SNP array typing of patient shows duplication on the short arm, internal boundaries of the duplication in 16p13.3 with minimum (2,929,908e3,955,374) and maximum (2,911,136e3,969,510) breakpoints. The 1025e1058 Kb region of gain contained 23 OMIM genes and 31 RefSeq genes. (C) SNP array profile of the mother from chromosome 16 shows duplication on 16p13.3 with minimum (2,963,260e3,955,374) and maximum (2,910,304e3,969,510) breakpoints. The 992e1059 Kb region of gain contained the same 23 OMIM genes as the patient's.
a pregnancy in which one has a mild intellectual disability may wish to consider microarray testing for a chromosome copy number change. In summary, we report a very rare case of maternally inherited 16p13.3 duplication. Our study provides additional information that contributes to the understanding and delineation of 16p13.3 duplication syndrome. Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics statement We received written informed consent from the patient's parents. Acknowledgment This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning(grant 2014R1A1A1007569)
References Chen, J.L., Yang, Y.F., Huang, C., Wang, J., Yang, J.F., Tan, Z.P., 2012. Clinical and molecular delineation of 16p13.3 duplication in a patient with congenital heart defect and multiple congenital anomalies. Am. J. Med. Genet. A 158a, 685e688. Dallapiccola, B., Bernardini, L., Novelli, A., Mingarelli, R., 2009. Expanding the phenotype of duplication of the Rubinstein-Taybi region on 16p13.3. Am. J. Med. Genet. A 149a, 2867e2870. Demeer, B., Andrieux, J., Receveur, A., Morin, G., Petit, F., Julia, S., Plessis, G., MartinCoignard, D., Delobel, B., Firth, H.V., Thuresson, A.C., Lanco Dosen, S., Sjors, K., Le Caignec, C., Devriendt, K., Mathieu-Dramard, M., 2013. Duplication 16p13.3 and the CREBBP gene: confirmation of the phenotype. Eur. J. Med. Genet. 56, 26e31. Feenstra, I., Fang, J., Koolen, D.A., Siezen, A., Evans, C., Winter, R.M., Lees, M.M., Riegel, M., de Vries, B.B., Van Ravenswaaij, C., 2006. European cytogeneticists association register of unbalanced chromosome aberrations (ECARUCA); an online database for rare chromosome abnormalities. Eur. J. Med. Genet. 49, 279e291. Friedman, J.M., Baross, A., Delaney, A.D., Ally, A., Arbour, L., Armstrong, L., Asano, J., Bailey, D.K., Barber, S., Birch, P., Brown-John, M., Cao, M., Chan, S., Charest, D.L., Farnoud, N., Fernandes, N., Flibotte, S., Go, A., Gibson, W.T., Holt, R.A., Jones, S.J., Kennedy, G.C., Krzywinski, M., Langlois, S., Li, H.I., McGillivray, B.C., Nayar, T., Pugh, T.J., Rajcan-Separovic, E., Schein, J.E., Schnerch, A., Siddiqui, A., Van Allen, M.I., Wilson, G., Yong, S.L., Zahir, F., Eydoux, P., Marra, M.A., 2006.
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Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am. J. Hum. Genet. 79, 500e513. Gilbert, F., 1999. Disease genes and chromosomes: disease maps of the human genome. Chromosome 16. Genet. Test. 3, 243e254. Li, Z., Liu, J., Li, H., Peng, Y., Lv, W., Long, Z., Liang, D., Wu, L., 2013. Phenotypic expansion of the interstitial 16p13.3 duplication: a case report and review of the literature. Gene 531, 502e505. Marangi, G., Leuzzi, V., Orteschi, D., Grimaldi, M.E., Lecce, R., Neri, G., Zollino, M., 2008. Duplication of the Rubinstein-Taybi region on 16p13.3 is associated with a distinctive phenotype. Am. J. Med. Genet. A 146A, 2313e2317. Martin, J., Han, C., Gordon, L.A., Terry, A., Prabhakar, S., She, X., Xie, G., Hellsten, U., Chan, Y.M., Altherr, M., Couronne, O., Aerts, A., Bajorek, E., Black, S., Blumer, H., Branscomb, E., Brown, N.C., Bruno, W.J., Buckingham, J.M., Callen, D.F., Campbell, C.S., Campbell, M.L., Campbell, E.W., Caoile, C., Challacombe, J.F., Chasteen, L.A., Chertkov, O., Chi, H.C., Christensen, M., Clark, L.M., Cohn, J.D., Denys, M., Detter, J.C., Dickson, M., Dimitrijevic-Bussod, M., Escobar, J., Fawcett, J.J., Flowers, D., Fotopulos, D., Glavina, T., Gomez, M., Gonzales, E., Goodstein, D., Goodwin, L.A., Grady, D.L., Grigoriev, I., Groza, M., Hammon, N., Hawkins, T., Haydu, L., Hildebrand, C.E., Huang, W., Israni, S., Jett, J., Jewett, P.B., Kadner, K., Kimball, H., Kobayashi, A., Krawczyk, M.C., Leyba, T., Longmire, J.L., Lopez, F., Lou, Y., Lowry, S., Ludeman, T., Manohar, C.F., Mark, G.A., McMurray, K.L., Meincke, L.J., Morgan, J., Moyzis, R.K., Mundt, M.O., Munk, A.C., Nandkeshwar, R.D., Pitluck, S., Pollard, M., Predki, P., Parson-Quintana, B., Ramirez, L., Rash, S., Retterer, J., Ricke, D.O., Robinson, D.L., Rodriguez, A., Salamov, A., Saunders, E.H., Scott, D., Shough, T., Stallings, R.L., Stalvey, M., Sutherland, R.D., Tapia, R., Tesmer, J.G., Thayer, N., Thompson, L.S., Tice, H.,
Torney, D.C., Tran-Gyamfi, M., Tsai, M., Ulanovsky, L.E., Ustaszewska, A., Vo, N., White, P.S., Williams, A.L., Wills, P.L., Wu, J.R., Wu, K., Yang, J., Dejong, P., Bruce, D., Doggett, N.A., Deaven, L., Schmutz, J., Grimwood, J., Richardson, P., Rokhsar, D.S., Eichler, E.E., Gilna, P., Lucas, S.M., Myers, R.M., Rubin, E.M., Pennacchio, L.A., 2004. The sequence and analysis of duplication-rich human chromosome 16. Nature 432, 988e994. Mattina, T., Palumbo, O., Stallone, R., Pulvirenti, R.M., Di Dio, L., Pavone, P., Carella, M., Pavone, L., 2012. Interstitial 16p13.3 microduplication: case report and critical review of genotype-phenotype correlation. Eur. J. Med. Genet. 55, 747e752. Roelfsema, J.H., Peters, D.J., 2007. Rubinstein-Taybi syndrome: clinical and molecular overview. Expert Rev. Mol. Med. 9, 1e16. Thienpont, B., Bena, F., Breckpot, J., Philip, N., Menten, B., Van Esch, H., Scalais, E., Salamone, J.M., Fong, C.T., Kussmann, J.L., Grange, D.K., Gorski, J.L., Zahir, F., Yong, S.L., Morris, M.M., Gimelli, S., Fryns, J.P., Mortier, G., Friedman, J.M., Villard, L., Bottani, A., Vermeesch, J.R., Cheung, S.W., Devriendt, K., 2010. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J. Med. Genet. 47, 155e161. Thienpont, B., Breckpot, J., Holvoet, M., Vermeesch, J.R., Devriendt, K., 2007. A microduplication of CBP in a patient with mental retardation and a congenital heart defect. Am. J. Med. Genet. A 143A, 2160e2164. Tuysuz, B., van Bon, B.W., Alp, Z., Guzel, Z., Veltman, J.A., de Vries, B.B., 2012. A microduplication of the Rubinstein-Taybi region on 16p13.3 in a girl with a bilateral complete cleft lip and palate and severe mental retardation. Clin. Dysmorphol. 21, 204e207.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
Maternally inherited autosomal dominant intellectual disability caused by 16p13.3 microduplication Cha Gon Lee a, *, Eunhae Cho b, Young Min Ahn a a b
Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, Seoul, Republic of Korea Green Cross Genome, Yongin, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 October 2015 Received in revised form 4 February 2016 Accepted 6 February 2016 Available online 9 February 2016
A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of RubinsteineTaybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a 1 Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient's mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome. © 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Chromosome 16p13.3 duplication syndrome Maternal inheritance Autosomal dominant Intellectual disability CREBBP
1. Introduction
2. Clinical data
A 16p13.3 duplication syndrome has been recently suggested as a novel recognizable syndrome as a reciprocal microduplication disease of RubinsteineTaybi syndrome (Thienpont et al., 2010). To date, only about 25 cases have been reported (Chen et al., 2012; Dallapiccola et al., 2009; Demeer et al., 2013; Friedman et al., 2006; Li et al., 2013; Marangi et al., 2008; Mattina et al., 2012; Thienpont et al., 2007, 2010; Tuysuz et al., 2012). This duplication involves the RubinsteineTaybi critical region and includes the CREBBP (cyclic adenosine monophosphate [cAMP]eresponse element-binding protein [CREB]-binding protein) gene. Clinical features include mild-to-moderate developmental delay, normal growth, characteristic facial features, mild arthrogryposis with camptodactyly and proximally implanted small thumb. Most duplications have been reported de novo (Thienpont et al., 2010). Here, we describe a boy and his mother with an approximately 1 Mb-sized duplication of 16p13.3, identified by single nucleotide polymorphism (SNP) array testing. He and his mother both displayed intellectual disability.
2.1. Patient
* Corresponding author. Department of Pediatrics, Eulji General Hospital, College of Medicine, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711, Republic of Korea E-mail address: [email protected] (C.G. Lee). http://dx.doi.org/10.1016/j.ejmg.2016.02.005 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved.
An 11-year-old boy visited the pediatric neurology clinic of Eulji General Hospital with maternally inherited intellectual disability on December 30, 2014. He was born vaginally after 37 and 1/7th weeks of gestation, weighing 2500 g (10e25th percentile), length of 43 cm (10e25th percentile), and an occipitofrontal circumference of 33 cm (25e50th percentile) from non-consanguineous Korean parents. His mother and father were 26 and 39 years of age, respectively (Fig. 1A). Except for the mother, the family had no history of neurologic disease or developmental delay. No feeding difficulties or hypotonia occurred during early infancy. He had received frequent admissions and treatments for respiratory, gastrointestinal, and upper urinary tract infections during infancy. He had global mild developmental delay, but did not show psychiatric, sleep, and behavior problems. In a physical examination at 11-years-of-age, he showed normal growth, with a body weight of 38.1 kg (0.19, standard deviation score, SDS), height of 151.3 cm (0.96 SDS), body mass index (BMI) of 16.64 kg/m2 (0.81 SDS), and head circumference of 50 cm (0.87 SDS). He had upslanted palpebral fissure, mild ptosis and low-set ears (Fig. 1B and C). Extremities were featureless (Fig. 1D and E). Other neurological examinations were normal. His first
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Fig. 1. Pedigree and photographs. (A) Pedigree of the family with maternal inherited intellectual disability. The black arrow indicates the proband. Darkened symbols represent affected members. Stars indicate sampled subjects. (BeC) Patient facial photographs at 11-years-of-age show the up-slanted palpebral fissure, ptosis and low-set ears. (D) Photograph of the patient's hands, illustrating absence of arthrogyposis-like features in both hands. (E) The skeletal bone age of the left wrist corresponds to according to the Greulich and Pyle standard at 11-years-of-age, which was suitable for his chronological age. (F) He had only cave of septum pellucidum without definite brain anomalies on 1.5 T magnetic resonance imaging. (GeH) The mother showed mild mid-face hypoplasia, round nose tip, and low-set ears. (I) She had mild flexion deformities of the proximal interphalangeal joints and proximally implanted small thumb with shorter distal phalanges in both hands.
neurodevelopmental evaluation was checked at 11-years-of-age. Intellectual functioning was measured by the Korean Wechsler Intelligence Scale for Children fourth edition (K-WISC-IV). He had moderate intellectual disability with Full Scale IQ (FSIQ) 49, verbal comprehension index (VCI) 47, perceptual reasoning index (PRI) 47, working memory index (WMI) 50, and processing speed index (PSI) 74. His social maturation quotient (SQ 52.73) and social age (SA) of 5.80 years also indicated moderate trainable intellectual disability. The Bender Gestalt test result was suggestive of motor incoordination and brain dysfunction. Laboratory tests including complete blood count, chemistry, electrolytes, and pituitary function test were within normal range. The results of an immunology blood test performed due to frequent infectious disease were nonspecific. Brain magnetic resonance imaging was normal, except for the cave of septum pellucidum (Fig. 1F). Voiding cystourethrogram revealed only a small diverticulum in the urinary bladder. 2.2. Patient's mother When the patient's mother first visited our clinic with her son, she was 38-years-old. She was the second child of healthy nonconsanguineous Korean parents. She had one healthy elder sister. There was no family history of neurologic disease or developmental delay except for her son. She had graduated high school and
married at 23-years-of-age. A physical examination showed a body weight of 54.5 kg (0.07 SD), height of 160.1 cm (0.13 SD), and body mass index of 21.26 kg/ m2 (0.05 SD). She had a dull facial expression and displayed characteristic facial features including mild mid face hypoplasia, round nose tip and low set ear (Fig. 1G and H). In our clinic, she was shy and quiet. She had camptodactyly and a proximally implanted small thumb with shorter distal phalanges in both hands (Fig. 1I). When evaluated at 26-years-of-age, she revealed a mild level of intellectual disability by the Korean Wechsler Adult Intelligence Scale (K-WAIS); FSIQ 59, VIQ 63, and PIQ 58. The clinical characteristics of the patient and his mother are summarized in Table 1. 3. Results 3.1. Patient Karyotyping, fluorescence in situ hybridization (FISH) for 22q11.2 and CGG repeat expansion analysis for FMR1 gene were all normal. Microarray analysis was carried out using the CytoScan 750 K high-resolution genotyping SNP microarray (Affymetrix, Santa Clara, CA, USA). Based on the human reference genome 37(NCBI37hg19) of the National Center for Biotechnology, the SNP assay revealed a region of gain spanning 1 Mb on chromosome 16p13.3 (Fig. 2B). The minimum start and stop point for this
212
C.G. Lee et al. / European Journal of Medical Genetics 59 (2016) 210e214
Table 1 Clinical characteristics of the patient, compared with reported common features of dup16p13.3. Trait
Proband
Mother
Previous reports (n ¼ 25)
Gender Inheritance Duplication size Small for gestational age Postnatal failure to thrive Intellectual disability (mild:moderated:severe) Behavioral problems Microcephaly/Macrocephaly Facial abnormalities Ptosis Blepharophimosis Upslanted palpebral fissure Bifid uvula: Cleft palate Low-set ears: Protruting ear: Dysplastic ears Midface hypoplasia: Bullbous nose tip Hand abnormalities Proximally implanted small thumb Camptodactyly Short finger Structural brain anomaly Structural cardiovascular anomalies
Male maternal 1025e1058 Kb none none moderate (K-WISC-IV, FSIQ 49) none none
Female ND 992Kbe1,059 Mb none none mild (K-WAIS-III, FSIQ 59) none none
M (17), F (8) de novo (22), inherited (2), ND (1) 375Kbe6.5 Mb 5/22 5/25 21/23 (5:15:1) 9/19 3/22 (3:0)
ptosis none upslanted palpebral fissure none low-set ears none
none none none none low-set ears mild midface hypoplasia, round nose tip
none none none cave of septum pellucidum none
proximally implanted small thumbs camptodactyly shorter distal phalanges ND ND
11/25 16/25 16/25 8/25 (2:5) 18/25 (10:7:9) 18/25 (15:7) 13/25 14/23 14/23 5/25 6/12 7/19 (ASD 4, VSD 2, TOF 1, dextrocardia1)
ND: no data available; K-WISC-IV; Korean Wechsler Intelligence Scale for Children fourth edition, KeWISCeIII: Korean Wechsler Adult Intelligence Scale third edition, FSIQ: full-scale intelligence quotient, ASD; atrial septal defect, TOF; tetralogy of Fallot.
duplication was estimated at 2,929,908 and 3,955,374, respectively, and the maximum breakpoint at 2,911,136 and 3,969,510, respectively. The size was estimated at 1025e1058 Kb and this region contained 23 OMIM genes and 31 RefSeq genes including CREBBP [NM 004380, MIN 600140]. The clinical and cytogenetic data was reported as case ID 5210 in the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) public database (www.ecaruca.net) (Feenstra et al., 2006). 3.2. Patient's parents G-banding analysis of the father and mother was achieved at a resolution above 550 bands. The results were normal, being 46,XY and 46,XX, respectively. SNP microarray analysis of the mother revealed a region of gain spanning about 992e1059 Kb on chromosome 16 with estimated minimum start and stop point for this gain at 2,963,260 and 3,955,374, respectively, and maximum breakpoint at 2,910,304 and 3,969,510, respectively (Fig. 2C). This region of gain contained 23 OMIM genes and 30 RefSeq genes. The gene list was the same as the patient's, except for the FLYWCH2 [NM 001142499] gene located on the starting breakpoint boundary. The difference of starting breakpoint between the patient and his mother was due to the SNP array probes. Probes are arrayed across the genome and signal intensity is used to identify regions that vary in copy number from what is expected. The density of probes at a given locus will determine resolution and therefore the extent of uncertainty. Because DNA between probes is not assayed by probebased experiments, there is no way to capture the precise location of variant boundaries. This necessarily results in fuzzy starting endpoints. The data of patient's mother was also submitted in the aforementioned public database as ECARUCA case ID 5211. 4. Discussion Many genetic conditions are related to changes in particular genes on chromosome 16 (Gilbert, 1999). The p13.3 regions on chromosome 16 are about 8 Mbp and harbor 107 genes (Martin et al., 2004). This region harbors chromosome 16p13.3 deletion syndrome, also known as RubinsteineTaybi syndrome (Roelfsema and Peters, 2007). The 16p13.3 duplication syndrome has recently
been recognized as a microduplication syndrome that is reciprocal to RubinsteineTaybi syndrome (Thienpont et al., 2010). The CREBBP gene is believed to represent the dosage sensitive critical gene responsible for these reciprocal duplication and deletion syndrome (Mattina et al., 2012; Roelfsema and Peters, 2007). The patient and his mother both had the approximate 1 Mb duplication on chromosome 16p13.3 (Fig. 2). These regions contained dosage changes of 23 common OMIM genes, included the well-known dosage sensitive CREBBP gene [NM 004380, MIN 600140] and several possible morbid genes, such as DNASE1 [NM 005223, MIM 152700], SLX4 [NM 032444, MIM 125505], MEFV [NM 000243, MIM 608107], and THOC6 [NM 024339, MIM 615403]. Known clinical features include normal growth, mild-to-moderate developmental delay, small and proximally implanted thumbs, mild arthrogryposis with camptodactyly, and dysmorphic facial features (ptosis, narrow palpebral fissures, up-slanted palpebral fissure, mid face hypoplasia, bullous nose tip) and are occasionally associated with heart defects, submucous cleft palate anomalies, and eye anomalies (strabismus, blepharophimosis, and ptosis) (Demeer et al., 2013; Li et al., 2013; Mattina et al., 2012; Thienpont et al., 2010; Tuysuz et al., 2012). The 23 genes were all candidate disease-causing genes responsible for the phenotype of our patient. In all patients reported so far, the smallest region of overlap contained only the CREBBP gene (Mattina et al., 2012). The actual gene that is the major dosage sensitive gene in 16p13.3 duplication syndrome is CREBBP. However, the dosage change of additional genes in this region probably accounts for the variable clinical features of this syndrome. In the present case, the patient and the mother showed normal growth and mild-to-moderate intellectual disability. Mild ptosis/upslanted palperbral fissure were apparent in the patient and mid-face hypoplasia, bulbous nose tip, camptodactyly/proximally implanted small thumb/shorter distal phalanges in his mother. Thus, the patient and his mother shared intellectual disability and low-set ears as common features (Table 1). The penetrance of this duplication seems variable, since two cases with inherited transmission involved normal carrier parents. Nevertheless, since most reported duplications arose de novo, there does appear to be a strongly reduced reproductive fitness associated with this genotype (Thienpont et al., 2010). A couple planning
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Fig. 2. Schematic diagram and SNP array results. (A) Diagrams amplified the common breakpoints regions on chromosome 16p13.3 (from 992 Kb to 1058 Kb) and showed the common genes of patient and his mother. (B) The SNP array typing of patient shows duplication on the short arm, internal boundaries of the duplication in 16p13.3 with minimum (2,929,908e3,955,374) and maximum (2,911,136e3,969,510) breakpoints. The 1025e1058 Kb region of gain contained 23 OMIM genes and 31 RefSeq genes. (C) SNP array profile of the mother from chromosome 16 shows duplication on 16p13.3 with minimum (2,963,260e3,955,374) and maximum (2,910,304e3,969,510) breakpoints. The 992e1059 Kb region of gain contained the same 23 OMIM genes as the patient's.
a pregnancy in which one has a mild intellectual disability may wish to consider microarray testing for a chromosome copy number change. In summary, we report a very rare case of maternally inherited 16p13.3 duplication. Our study provides additional information that contributes to the understanding and delineation of 16p13.3 duplication syndrome. Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics statement We received written informed consent from the patient's parents. Acknowledgment This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning(grant 2014R1A1A1007569)
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