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 : RNA Bain N, Kamien B. 2015. A familial 7q36.3 RBM33 SHH Binding Motif 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 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; 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 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 þþ Intellectual disability þ ? borderline borderline Seizures þ Broad forehead þþþþ Plagiocephaly þþ 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. genes in this region: SHH with a predicted haploinsufficiency score of 16.3, and RBM33 with a predicted haploinsufficiency score of Other Family History 59.5. The entire SHH gene is duplicated whereas the RBM33 gene is disrupted at a breakpoint located between intron 5 and intron 16 of The parents of Patient I:2 were reported to have had normal the largest transcript RBM33-007 (accessed through ENSEMBL) intellect. Patient I:2 has five siblings who have not been examined [Flicek et al., 2013]. Patient II:3 is entered in to DECIPHER as or had chromosomal investigations, but apparently have normal patient 264480. The FISH studies confirmed both duplications in intellect. Patient I:2 has a younger sister born with a cleft lip and Patients II:3 and III:6, but only the 7q36.3 duplication in Patients palate and bilateral sensorineural deafness. Patient I:2’s younger II:4 and I:2. The FISH on metaphase cells showed no evidence of brother was reported to have macrocephaly but details are not interchromosomal insertion and tandem duplication of this region available. Individuals II:1 and II:2 were reported to have OFCs on is the most likely mechanism. the 50th centile and Patient II:2 had a normal cranial MRI. DISCUSSION MATERIALS AND METHODS In this clinical report, we propose that a familial 7q36.3 micro- A CGH microarray analysis was performed using a 60 k Oligo ISCA duplication involving SHH and RBM33 is associated with ACC, design analyzed with BlueMulti v2.5 software (BlueGnome, Ful- macrocephaly, broad forehead, widely spaced eyes, and mild bourn, Cambridge, UK). The FISH studies were performed on intellectual disability or borderline intellectual functioning across interphase nuclei using the RP11-478P15 probe for duplications at three generations. There are no known genes in the 1q31.1 dupli- 1q31.1 and the probe RP11-52501 for duplications at 7q36.3 cation and this duplication was not detected in Patients II:4 and I:2 2204 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

We conclude that this duplication is a highly unlikely cause of these findings, although we cannot exclude a position effect or gene regulatory disruption from this duplicated material. Little is known about the function of RBM33. Based on data from BioGPS, SAGE (accessed via Genecards) and EMBL-EBI databases, RBM33 appears to be mildly expressed in multiple sites including the CNS, particularly in the cerebellum. Human RBM33 expression is reported in the brain as early as nine post-conception weeks in the BrainSpan Atlas of the Developing Human Brain. Unfortunately, earlier embryonic gene expression data are lacking. According to DECIPHER, the haploinsufficiency index of RBM33 is 59.5 making this gene a less likely candidate for ACC or intellectual disability. However, we cannot be certain that RBM33 disruption does not contribute to the phenotype in this family and further experimental evidence from vertebrate studies would be required to fully assess the role of RBM33 in brain development. SHH is highly expressed within the developing nervous system. Mutations in SHH are the most common cause of non-chromo- somal holoprosencephaly (HPE). The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences [Hahn and Barnes 2010; Hahn et al., 2010; O’Driscoll et al., 2010; Solomon et al., 2010, 2012]. Where SHH mutations do not appear to cause any brain malformations (termed microform of HPE), variable clinical features include microcephaly, midface hypoplasia, hypotelorism, a flat or sharp nasal bridge, a single maxillary central incisor, or neurocognitive disturbances. It is worth noting that the phenotype of the current patients is opposite to the microform HPE phenotype in some respects. The finding of ACC in the presence of Chiari malformations has been reported [Barkovich and Norman 1988; Galarza et al., 2010]. One hypothesis regarding Chiari malformations is that underde- velopment of occipital somites of the para-axial mesoderm pro- duces a diminutive, overcrowded posterior fossa [Urbizu et al., 2013]. This hypothesis was advanced by experiments that showed vitamin A could induce Chiari malformations in vertebrates [Marin-Padilla and Marin-Padilla, 1981]. While the interactions between SHH and retinoic acid signaling are complex, and can vary between species, retinoic acid is able to facilitate SHH signaling [Ribes et al., 2006, 2009]. Given this information, it is possible that SHH overexpression may contribute to Chiari malformations. Duplications of SHH are rare. Four patients were identified in the DECIPHER database to have overlapping 7q36.3 duplications with the proband. Phenotypes described include intellectual dis- ability and major congenital abnormalities with no description of abnormalities of the corpus callosum. However, the duplications in these patients involved much larger regions, ranging in size from 5.74 Mb to 42.64 Mb and this makes direct comparison or extrap- FIG. 3. Single-shot half-Fourier turbo spin-echo magnetic reso- olation with the family presented in this report difficult. nance images of the fetus at 31 weeks. A: Axial image shows According to the Database of Genomic Variants (DGV), one complete agenesis of the corpus callosum and colpocephaly. B: control subject has been reported with a duplication involving SHH Coronal images demonstrate elevation of the third ventricle, and part of RBM33 [MacDonald et al., 2013]. No clinical data are vertical orientation of the lateral ventricles and absence of the available about this individual other than that the subject was corpus callosum. chosen because of a normal phenotype (no other control individ- ual, from over 15,000 individuals, had a duplication in this region). In addition, no neuroimaging was performed in this individual. WONG ET AL. 2205

FIG. 4. Sagittal T2 and axial T2 weighted images, and diffusion tensor imaging from patient III:6. A and B: Axial images demonstrating widely spaced, parallel ventricles indicative of agenesis of the corpus callosum. The green tracts on diffusion tensor imaging represent axons that have formed but do not cross the midline (Probst bundles). C: The sagittal MRI shows complete agenesis of the corpus callosum, and a Chiari type I malformation. D: Diffusion Tensor Imaging tractography (20 diffusion directions; syngo Seimens) demonstrates longitudinal orientated tracts (in green) that do not cross the midline representing Probst bundles.

The effects and consequences of duplications and overexpres- the patients described in DECIPHER with larger duplications sion of SHH in humans have been rarely reported in the literature. involving SHH. The 2-year-old boy had developmental delay Bendavid et al. [2009] examined 111 patients with HPE using array and dysmorphic features similar to those observed in the present CGH (aCGH). They had normal standard karyotypes and 28 went family, including macrocephaly, a broad forehead, and widely on to have an aCGH abnormality. One of these 28 patients had spaced eyes, although the authors did not publish photos. Inter- semilobar HPE and a duplication at chromosome 7q. The genomic estingly, an autopsy performed on the fetus and a post-natal co-ordinates of this patient (converted to GRCh37/hg19) were ultrasound performed on the boy with muscular hypertrophy Chr7:154,993,054–155,865,024. This 0.93 Mb duplication contains did not show structural brain abnormalities [Kroeldrup et al., five genes including SHH and RBM33 [Bendavid et al., 2009]. 2012]. A recent report of particular interest describes siblings (a 2-year- An additional report by Bear et al. [2012] described a patient old boy and an aborted fetus) with a 0.3 Mb duplication at 7q36.3 with a de novo 0.4 Mb duplication arr 7q36.3(154,977,855– involving both SHH and RBM33 and no other genes [Kroeldrup 155,372,260) 3 (hg 18). This duplication contained three genes, et al., 2012]. The microduplication occurred de novo and its SHH, CNPY1, and RBM33. This patient had an encephalocele and presence in siblings suggested gonadal mosaicism. In these patients, no other structural brain malformations or congenital abnormali- RBM33 is wholly duplicated, whereas the family members de- ties [Bear et al., 2012]. The reason why other patients with SHH scribed in our report have a partial duplication of RBM33 that duplications have heterogenous phenotypes (HPE, muscular hy- possibly disrupts a copy of this gene. The boy and the fetus in the pertrophy, encephalocele, or normal phenotype) is unclear. report by Kroeldrup et al. [2012] had muscular hypertrophy. The Mouse models with Shh duplications have not been published to authors concluded that the over expression of SHH may be the best assist with interpretation of the current results. Nevertheless, explanation for the observed clinical findings in these siblings. vertebrate studies demonstrate that SHH has roles in axonal Muscular hypertrophy was not observed in the present family nor outgrowth, axonal attraction and axonal repulsion at different 2206 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

FIG. 5. Cranial MRI from Patient II:4 and CT from Patient I:2. A: Sagittal T1 weighted image showing complete agenesis of the corpus callosum and a Chiari type I malformation. B: Axial T2 weighted image demonstrating Probst bundles (arrowed). C: Sagittal CT showing complete agenesis of the corpus callosum. D: Axial CT showing widely spaced lateral ventricles indicative of agenesis of the corpus callosum.

embryological times [Aviles et al., 2013]. The SHH protein is Rosenfeld et al., 2010]. Of relevance to the present study, reciprocal involved with the crossing of spinal commissural axons in the repression has been described between WNT/BMP dorsally and floor plate [Ulloa and Briscoe, 2007], and its absence permits optic SHH ventrally [Ohkubo et al., 2002; Shimogori et al., 2004; Storm nerve decussation at the chiasma [reviewed in Erskine and Herrera, et al., 2006; Aviles et al., 2013], meaning that a gain of SHH could 2007]. Since only the corpus callosum was affected in our patient restrict the dorsal component of the commissural plate and disrupt cohort, it is unlikely that SHH overexpression and disruption of corpus callosum formation. Importantly, through a series of axonal guidance or repulsion are the principal mechanisms of ACC experiments in which additional Shh was introduced into the here. Instead, based on vertebrate studies, we propose that a dorsal extent of the zona limitans intrathalamica of embryonic combination of morphogen patterning influences and mainte- mice, immediately caudal to the developing commissural plate, nance of precursor cell populations have contributed to the present researchers found that the dorsal telencephalic midline failed to condition. properly invaginate and the cortical hem, including WNT expres- Firstly, SHH is induced at the prechordal mesoderm at the sion, which is required for corpus callosum crossing, was disrupted neuroepithelial midline of the developing embryo. Hence, at the [Himmelstein et al., 2010]. In contrast, this gain in Shh also caused midline of the prosencephalon in vertebrates, a gain in SHH roof plate expansion, potentially contributing to macrocephaly. promotes expansion of the forebrain and the overlying facial Similar disruptions of the telencephalon have been observed in primordium that leads to macrocephaly, broad foreheads and murine mutants in which SHH is over-active [Eggenschwiler et al., widely spaced eyes, consistent with that observed in our patient 2001; Stottmann et al., 2009; Tran et al., 2008]. Together, these cohort [Hu and Helms, 1999; Hu and Marcucio, 2009]. experiments demonstrate how duplication of SHH can cause Secondly, during embryonic development, a coronal oblique macrocephaly, widely spaced eyes, and disruption of the commis- plane of tissue develops from the anterior neural ridge that sural plate required for corpus callosum formation. occupies the area between the dorsal pallium and ventral subpal- Probst bundles are common in ACC and are formed by com- lium of the telencephalon, termed the commissural plate [Rakic missural axons that failed to cross the midline due to malforma- and Yakovlev, 1968; Moldrich et al., 2010]. Precise dorsoventral tions of the commissural plate or localized axon guidance deficits patterning at the commissural plate is critical for the formation of [Kamnasaran 2005; Hetts et al., 2006; Schell-Apacik et al., 2008]. the corpus callosum by establishing domains of axon guidance cues Therefore, the presence of Probst bundles in Patients II:3, II:4, and and glial cell populations that appear to serve as a path for III:6 is consistent with the hypothesis that the commissural plate commissural axon growth across the midline [Lent et al., 2005; failed to adequately form to permit crossing of the growing Suarez et al., 2014]. Major morphogens contributing to this commissural axons. patterning include fibroblast growth factor 8 (FGF8) emerging While the present clinical report and previous vertebrate studies from the anterior neural ridge, Wingless type (WNT)/Bone mor- point to a role for SHH overexpression disrupting the commissural phogenetic protein (BMP) from the medial pallium and cortical plate formation thereby leading to ACC and Probst bundle forma- hem, and SHH from the medial subpallium. These morphogens tion, further clinical reports of small chromosomal duplications permit later specification of the commissural plate via zinc finger involving SHH and/or RBM33, along with rodent transgenic studies, protein of the cerebellum 2 (ZIC2), empty spiracles homeobox are ultimately required to dissect out the roles of these genes. (EMX 1 and 2) and sine oculis-related homeobox 3 homolog SIX3 ( ) [Moldrich et al., 2010; Suarez et al., 2014]. Their importance ACKNOWLEDGMENTS clinically is revealed by reports that mutations in ZIC2, SIX3, and FGF8 result in HPE [Brown et al., 1998, 2001; Wallis et al., 1999; We thank the patients and their families for their cooperation. WONG ET AL. 2207

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