A Familial 7Q36.3 Duplication Associated with Agenesis of The

A Familial 7Q36.3 Duplication Associated with Agenesis of The

CLINICAL REPORT A Familial 7q36.3 Duplication Associated with Agenesis of the Corpus Callosum Keith Wong,1 Randal Moldrich,2 Matthew Hunter,1,3 Matthew Edwards,4 David Finlay,5 Sheridan O’Donnell,3 Tom MacDougall,6 Nicole Bain,7 and Benjamin Kamien1,3* 1The University of Newcastle, School of Medicine and Public Health, Newcastle, New South Wales, Australia 2The University of Queensland, The UQ Centre for Clinical Research, Brisbane, Queensland, Australia 3Hunter Genetics, Newcastle, New South Wales, Australia 4Paediatrics, School of Medicine, University of Western Sydney, Sydney, New South Wales, Australia 5Faculty of Science, Technology, and Engineering, LaTrobe University, Bundoora, Victoria, Australia 6Department of Radiology, John Hunter Hospital, Newcastle, New South Wales, Australia 7Hunter Area Pathology Service (HAPS), John Hunter Hospital, Newcastle, New South Wales, Australia Manuscript Received: 17 December 2014; Manuscript Accepted: 19 April 2015 Small chromosomal duplications involving 7q36.3 have rarely been reported. This clinical report describes four individuals How to Cite this Article: from a three-generation family with agenesis of the corpus Wong K, Moldrich R, Hunter M, Edwards callosum (ACC) and a 0.73 Mb duplication of 7q36.3 detected M, Finlay D, O’Donnell S, MacDougall T, by array CGH. The 7q36.3 duplication involves two genes: RNA Bain N, Kamien B. 2015. A familial 7q36.3 RBM33 SHH Binding Motif Protein 33 ( ) and Sonic Hedgehog ( ). duplication associated with agenesis of the Most affected family members had mild intellectual disability or corpus callosum. borderline intellectual functioning, macrocephaly, a broad fore- Am J Med Genet Part A 167A:2201–2208. head, and widely spaced eyes. Two individuals had a Chiari type I malformation. This is the first family reported with ACC asso- ciated with a small duplication of these genes. While we cannot establish causation for the relationship between any single gene and Chiari type I malformation involving three generations in an and the ACC in this family, there is a role for SHH in the autosomal dominant pattern using array CGH. formation of the corpus callosum through correct patterning and assembly of the commissural plate, and these data concur CLINICAL REPORTS with vertebrate studies showing that a gain of SHH expands the facial primordium. Ó 2015 Wiley Periodicals, Inc. The pedigree is shown in Figure 1 and patient photos are shown in Figure 2. Clinical summaries of the patients are listed in Table I. All Key words: sonic hedgehog; SHH; agenesis of the corpus affected patients had complete ACC with Probst bundles (Figs. 3– callosum; Chiari malformation; macrocephaly; chromosome 5). None of the patients had a history of in utero alcohol exposure. 7q36.3; RBM33 Patient II:3 Patient II:3 was the third child born to non-consanguineous parents. In her first year of life, she presented to pediatric neurology services INTRODUCTION with increasing head size and at age 9 months, her OFC was 48.5 cm Failure of commissural axons to cross the cortical hemispheres during fetal development results in agenesis of the corpus callosum Keith Wong and Randal Moldrich contributed equally to this work. Conflict of interest: None. (ACC). Whether ACC occurs in isolation or as a syndrome, the à neurobiological causes of ACC can stem from problems with cell Correspondence to: Benjamin Kamien, Hunter Genetics, Newcastle, New South Wales, proliferation, differentiation, axon outgrowth, and guidance Australia. [Edwards et al., 2014]. Reflecting this diverse range of causes, E-mail: [email protected] enormous variability of cognition, executive function, language, Article first published online in Wiley Online Library and social interaction is found in individuals with ACC. Herein we (wileyonlinelibrary.com): 5 May 2015 have clinically and molecularly characterized a family with ACC DOI 10.1002/ajmg.a.37143 Ó 2015 Wiley Periodicals, Inc. 2201 2202 AMERICAN JOURNAL OF MEDICAL GENETICS PART A family history of ACC, and an equivocal earlier antenatal ultrasound result. This showed evidence of ACC, with colpo- cephaly, and midline ventricles (Fig. 3). She was delivered at 41 weeks gestation. Her birth weight was 3.01 kg (25th centile), birth length was 50.0 cm (75th centile), and OFC was 37.0 cm (90th centile). On examination at 13 months, her OFC was 52.5 cm (3.5 cm >97th centile), length was 77.3 cm (50th centile), and weight was 8.9 kg (5th centile). The rest of the examination was normal aside from a broad forehead. Her IPD was 4.5 cm (50th centile). An MRI with diffusion tensor FIG. 1. Patients who have the 7q36.3 duplication and agenesis imaging was performed at age 13 months (Fig. 4), which showed of the corpus callosum are indicated by black fill. No other the presence of Probst bundles. family members were tested for the 7q36.3 duplication. Patient II:4 (2.5 cm above the 98th centile). Subsequent CT investigation Patient II:4 is the younger sister of patient II:3. She had apparent showed ACC with a Chiari type I malformation. Serial OFC meas- macrocephaly at birth and then delayed developmental milestones. urements were persistently >98th centile. She had mild intellectual She later had increasing head size and serial OFC measurements disability throughout life. At age 16, she underwent the Wechsler throughout childhood were >98th centile (data not shown). A CT Abbreviated Scale of Intelligence (WASI), and achieved a verbal IQ scan in early childhood showed ACC. At 15 years of age, she score of 64 (1st centile), a performance IQ score of 61 (0.5 centile) underwent the WASI test, and achieved a verbal IQ score of 65 (1st and a full scale IQ score of 59 (0.3 centile). An MRI at age 17 years centile), a performance IQ score of 91 (21st centile), and a full-scale showed complete ACC, Probst bundles, and a Chiari type I malfor- IQ score of 75 (5th centile). Later that year, she developed acute mation. At age 27, examination showed a healthy female with an obstructive hydrocephalus. Emergency surgery was required to OFC of 59.5 cm (2 cm >98th centile), broad forehead, and an decompress the posterior fossa and a Chiari type I malformation interpupillary distance (IPD) of 6.5 cm (97th centile). was also diagnosed at this time. At 26 years of age, she had an OFC of 60.5 cm (3.5 cm >98th centile). Mild right sided weakness with increased reflexes were noted in the upper and lower limbs Patient III:6 associated with acute brain injury sustained at 15 years of age Patient III:6 is the first-born female offspring of Patient II:3. during the episode of acute hydrocephalus. Dysmorphic features Fetal MRI was performed at 31 weeks gestation because of the were subtle and include macrocephaly, widely spaced eyes (IPD FIG. 2. Photographs of family members demonstrating macrocephaly and broad foreheads. A, B: Individual I:2. C, D: Individual II:3. E, F: Individual II:4. G, H: Individual III:6. Individuals I:2, II:3, and II:4 had measurably widely spaced eyes. WONG ET AL. 2203 TABLE I. Clinical Features of Affected Family Members Family table II:3 III:6 II:4 I:2 Chromosomal duplications 1q31.1, 7q36.3 1q31.1, 7q36.3 7q36.3 7q36.3 Sex F F F F Age at recent review 26 6 months 25 54 Birth weight (kg) 3.49 3.01 3.03 n/a Birth OFC (cm) n/a 37.0 n/a n/a OFC at recent review (cm) 59.5 41.0 61.0 58.0 ACC þþþþ Chiari malformation þþÀ Intellectual disability þ ? borderline borderline Seizures ÀÀÀþ Broad forehead þþþþ Plagiocephaly þþÀ Widely spaced eyes þþþ 6.5 cm), plagiocephaly with facial asymmetry, and a broad fore- (Probes supplied by The Centre for Applied Genomics, Toronto, head. A cranial MRI performed at age 15 is shown in Figure 5. Canada). The DECIPHER database was used to view and interpret the chromosomal microduplications. Haploinsufficiency indexes Patient I:2 taken from the DECIPHER database were used. Low scores indicate a high predicted probability that a gene is haploinsufficient, i.e., Patient I:2 is the mother of Patient II:3 and II:4. She was slow in that deletion of one allele may be pathogenic [Firth et al., 2009; reaching her developmental milestones and did not do well at Huang et al., 2010]. Development expression data are from the school. This was in contrast to her five siblings who apparently Allen Developing Mouse Brain Atlas. achieved above average grades. After delivery of her first child at age 17 years, she experienced generalized seizures, which were managed with phenytoin and carbamazepine. She reported taking phenytoin RESULTS during all subsequent pregnancies. She was noted to have a large Array CGH performed while Patient II:3 was pregnant with head and broad forehead and underwent a cranial CT scan, which Patient III:6 detected a duplication at chromosome 1q31.1 found ACC. At 42 years of age, she underwent the WASI test, and spanning 0.51 Mb (minimum duplicated region—chr1:187,621, achieved a verbal IQ score of 78 (7th centile), a performance IQ 772–188,132,614; GRCh37/hg19). There are no genes in this score of 95 (37th centile), with a full scale IQ of 85 (16th centile). region. An additional duplication at chromosome 7q36.3 was She was examined at age 54 and her OFC was 58 cm (1 cm >98th detected spanning 0.73 Mb (minimum duplication region— centile). She had widely spaced eyes (IPD 6.5 cm), and a broad chr7:155,559,492–156,289,696; GRCh37/hg19). There are two forehead. A CT scan at age 52 years is shown in Figure 5.

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