3.4 | Clinical phenotypes of patients with a pathogenic CNV
Of 40 patients, seven (17.5%) were found to have a pathogenic CNV by CMA or LD-WGS (Table 3). The size of duplication or deletion region was between 312 Kb and 28.43 Mb.
Patient M-004 presented with severe intellectual disability, autistic behaviors, epilepsy, and dysmorphic facial features, and showed an 801 Kb deletion at 7q11.21. This region contains the AUTS2 gene, and the deletion of the AUTS2 gene has been reported to be associated with autism, intellectual disability, short stature, and microcephaly (Beunders et al., 2013).
M-017 presented with primary microcephaly and congenital heart disease, and showed a 2,790 Kb deletion at 9q34.3. This region was previously associated with 9q subtelomeric syndrome characterized by severe developmental delay, microcephaly, congenital heart disease, and seizure (Stewart, & Kleefstra, 2007).
M-048 presented with primary microcephaly and congenital heart disease, and displayed a 28.43 Mb duplication at 16p13.3p11.2. This region was registered at OMIM as associated with chromosome 16p11.2 duplication syndrome (MIM 614671). Patients with a 16p11.2 duplication have been reported to have motor delays, congenital anomalies, seizures, and microcephaly (Shinawi et al., 2010).
M-074 presented with primary microcephaly, epilepsy, and cleft palate, and carried a 368 Kb duplication at 6q25.3. This region contains theARID1B gene, which is a causative gene for Coffin-Siris syndrome, which is characterized by mental retardation and associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Patients with a ARID1Bduplication have been reported to show moderate developmental delays, hypotonia, and high-arched palate (Hoyer et al., 2012).
A girl (M-075) showing microcephaly with pontine and cerebellar hypoplasia by brain MRI was found to have a 2.8 Mb deletion at Xp11.4p11.3 (Figure 2). This region contains the CASK gene, and deletion of the CASK gene has been reported to be associated with mental retardation and microcephaly with disproportionate pontine and cerebellar hypoplasia in females (Hayashi et al., 2012).
M-116 presented with intellectual disability and autistic features, midline hypoplasia of the face, hypertrichosis, and bush eyebrows, and showed a 312 Kb deletion at 2q23.1. This region contains the MBD5gene, and deletion of the MBD5 gene has been reported to be associated with intellectual disability, seizures, significant speech impairment, and behavioral problems (Bonnet et al., 2013).