A 3.2 Mb deletion on 18q12 in a patient with childhood autism and high-grade myopia

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with unknown aetiology. Even though ASDs are suggested to be among the most heritable complex disorders, only a few reproducible mutations leading to susceptibility for ASD have been identified. In an attempt to identify ASD susceptibility genes through chromosome rearrangements, we investigated a female patient with childhood autism and high-grade myopia, and an apparently balanced de novo translocation, t(5;18)(q34;q12.2). Further analyses revealed a 3.2 Mb deletion encompassing 17 genes at the 18q break point and an additional deletion of 1.27 Mb containing two genes on chromosome 4q35. Q-PCR analysis of 14 of the 17 genes deleted on chromosome 18 showed that 11 of these genes were expressed in the brain, suggesting that haploinsufficiency of one or more genes may have contributed to the childhood autism phenotype of the patient. Identification of multiple genetic changes in this patient with childhood autism agrees with the most frequently suggested genetic model of ASDs as complex, polygenic disorders.

Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity

“…Although CELF4 was previously found disrupted in patients with overlapping phenotypes, 10, 13 no phenotype has been associated with the non-coding RNA LOC643542 , thus we find it highly likely that haploinsufficiency of CELF4 causes the described phenotype. CELF4 belongs to a family of evolutionary highly conserved genes.…”

“…We characterized the rearrangement with SNP array and next-generation sequencing (NGS) and found truncation of CELF4 , which has previously been suggested as a neurodevelopmental candidate gene. 13 This report illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental genes.…”

“…However, as illustrated in Table 1 there is a considerable phenotypic overlap with our patient. Gilling et al 13 reported a patient with childhood autism, severe myopia, and a de novo translocation, t(5;18)(q34;q12). The patient had normal intelligence (IQ 88) and no dysmorphic facial features.…”

“…19 In frog embryos ( Xenopus laevis ), Celf4 is solely expressed in the nervous system, including the optic veiscles, 20 suggesting an important role in both brain and eye development. Furthermore, Celf4 is highly expressed in mouse brain 13, 19, 21 and Celf4 insufficient transgenic mice develop convulsive seizures, hyperactivity, and late-onset body weight gain. 21, 22 Not only is CELF4 conserved from Drosphila to mouse and human, but the genomic landscape next to CELF4 is also evolutionary conserved 23 harboring ultra-conserved elements (UCE), 24 and it has been suggested that UCEs may be directly involved in neurodevelopmental disorders.…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 In 15 of these patients, the deletions were examined with chromosome analysis, and in the remaining 5 patients molecular investigations identified deletions ranging from 3.2 to 24 Mb in size. 9, 10, 12, 13 Common clinical findings included intellectual disability, behavioral disorders, seizures, eye manifestations, obesity, and mild or absent dysmorphic facial features.…”