Journal Article

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features

Egger, Gerald, Ayub, Muhammad, Ali, Ghazanfar, Ansar, Muhammad, Spiegelman, Dan, Mahmood, Huda, Christian, Mehtab, Laurent, Sandra, Brohi, Muhammad Qasim, So, Joyce, Ambalavanan, Amirthagowri, Waqas, Ahmed, Vincent, John B, Shaheen, Naseema, Amin-ud-din, Muhammad, Saqib, Muhammad Arif Nadeem, Ayaz, Muhammad, Leblond, Claire S, Rafiq, Muhammad Arshad, Ali, Nadir, Nanjiani, Zohair, Xiong, Lan, Johnson, Amelie, Mottron, Laurent, Khan, Falak Sher, Caron, Chantal, Fennell, Alanna, Rasheed, Saima, Vincent, Akshita K., Forgeot d’Arc, Baudouin

2015

Overview

Background Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. Methods Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. Results We identified two novel homozygous deletion mutations in VPS13B , firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the “friendly” demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. Conclusion We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

• Publisher: BioMed Central
• Subject: Abnormalities, Multiple - genetics / Autistic Disorder - genetics / Autistic Disorder - pathology / Base Sequence / Biomedical and Life Sciences / Biomedicine / Cytogenetics / Developmental Disabilities - classification / Developmental Disabilities - ethnology / Developmental Disabilities - genetics / Developmental Disabilities - pathology / Female / Fingers - abnormalities / Fingers - pathology / Gene Function / Genes, Recessive / Genotype / Haplotypes - genetics / Homozygote / Human Genetics / Humans / Intellectual Disability - classification / Intellectual Disability - ethnology / Intellectual Disability - genetics / Intellectual Disability - pathology / Male / Microcephaly - classification / Microcephaly - ethnology / Microcephaly - genetics / Microcephaly - pathology / Molecular Sequence Data / Muscle Hypotonia - classification / Muscle Hypotonia - ethnology / Muscle Hypotonia - genetics / Muscle Hypotonia - pathology / Myopia - classification / Myopia - ethnology / Myopia - genetics / Myopia - pathology / Obesity - classification / Obesity - ethnology / Obesity - genetics / Obesity - pathology / Pakistan / Pedigree / Phenotype / Research Article / Retinal Degeneration / Sequence Analysis, DNA / Sequence Deletion - genetics / Vesicular Transport Proteins - genetics