title: A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.
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.
authors.affiliation: NIHR Biomedical Research Centre, Oxford and Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
authors.forename: Alistair T
authors.initials: AT
authors.lastname: Pagnamenta
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Murray
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.forename: Elham
authors.initials: E
authors.lastname: Sadighi Akha
authors.forename: Victoria
authors.initials: V
authors.lastname: Harrison
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Kaseem
authors.initials: K
authors.lastname: Ajilogba
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Samantha J L
authors.initials: SJ
authors.lastname: Knight
mesh_terms: D018797:Cell Cycle Proteins; D002648:Child; D018389:Codon, Nonsense; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012998:Somalia
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins