A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss

Alistair T Pagnamenta,Jenny C Taylor,Usha Kini,Victoria Harrison,Louise S Bicknell,Andrew P Jackson,David A Keays,Helen Stewart,Jennie E Murray,Grace Yoon,Kaseem Ajilogba,Elham Sadighi Akha,Samantha J.L Knight

doi:10.1002/ajmg.a.35558

Abstract

Primary microcephaly is a genetically heterogeneous condition characterized by reduced head circumference (−3 SDS or more) and mild-to-moderate learning disability. Here, we describe clinical and molecular investigations of a microcephalic child with sensorineural hearing loss. Although consanguinity was unreported initially, detection of 13.7 Mb of copy neutral loss of heterozygosity (cnLOH) on chromosome 9 implicated the CDK5RAP2 gene. Targeted sequencing identified a homozygous E234X mutation, only the third mutation to be described in CDK5RAP2, the first in an individual of non-Pakistani descent. Sensorineural hearing loss is not generally considered to be consistent with autosomal recessive microcephaly and therefore it seems likely that the deafness in this individual is caused by the co-occurrence of a further gene mutation, independent of CDK5RAP2. Nevertheless, further detailed clinical descriptions of rare CDK5RAP2 patients, including hearing assessments will be needed to resolve fully the phenotypic range associated with mutations in this gene. This study also highlights the utility of SNP-array testing to guide disease gene identification where an autosomal recessive condition is plausible. © 2012 Wiley Periodicals, Inc.

Highlights

Mutations in ASPM and WDR62 account for the majority of patients with primary microcephaly [Bond et al, 2002; Nicholas et al, 2010]
In addition to the large regions of copy neutral loss of heterozygosity (cnLOH) on chr7p and chr9q, five other cnLOH loci of intermediate size (2–5 Mb) were identified. These were located at 3p24.3, 4q26, 5q21.1, 16p11.2, and Xq22.3. We searched these seven loci for genes noted in OMIM as being linked with deafness and we identified four genes (DFNA5, HOXA2, COL4A5, and PRPS1), none of these appeared to be a likely candidate based on their inheritance pattern or because the phenotype of our patient did not match
Our patient has significant bilateral sensorineural hearing loss. This manifestation is not generally considered to be consistent with autosomal recessive microcephaly and it is highly possible that the deafness may be caused by a further gene mutation, independent of CDK5RAP2

Summary

Introduction

Mutations in ASPM and WDR62 account for the majority of patients with primary microcephaly [Bond et al, 2002; Nicholas et al, 2010]. Five other causative genes are known but have only been reported in a few individuals A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss. Am J Med Genet Part A 158A:2577–2582. A recent study suggests CEP135 may be responsible for an eighth microcephaly locus on chromosome 4q12 [Hussain et al, 2012]. The fact that the majority of these microcephaly genes were mapped using consanguineous kindreds from Pakistan highlights the importance of the autozygosity mapping strategy in the AMERICAN JOURNAL OF MEDICAL GENETICS PART A understanding of this rare condition. As a consequence, it is unclear what clinical relevance these genes have in other populations

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Conclusion