title: The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.
abstract: Primary autosomal recessive microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly and intellectual disability. To date, 10 MCPH loci have been identified and due to the genetic heterogeneity of this condition, molecular testing for MCPH can be complicated. Our methods involved employing a next generation sequencing panel of MCPH-related genes allowing for the evaluation of multiple disease loci simultaneously. Next generation sequencing analysis of a 6 year old female with primary microcephaly identified novel compound heterozygous mutations (c.524_528del and c.4005-1G>A) in the CDK5RAP2 gene. A review of the published literature to date reveals that only three mutations have been previously reported in the CDK5RAP2 gene in the homozygous state in three Northern Pakistani and one Somali consanguineous MCPH families. Our patient represents the first non-consanguineous Caucasian individual to have been identified with CDK5RAP2-related MCPH. As only a handful of patients have been reported in the literature with CDK5RAP2-related MCPH, we anticipate the identification of individuals with CDK5RAP2 mutations from all ethnic backgrounds will continue. Our patient contributes to the ethnic and genotypic spectrum of CDK5RAP2-related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations. Our results also highlight the utility of multi-gene sequencing panels to elucidate the etiology of genetically heterogeneous conditions.
authors.affiliation: Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave, MC 0077, Chicago, IL 60637, USA. Electronic address: ctan@bsd.uchicago.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Tan
authors.affiliation: Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave, MC 0077, Chicago, IL 60637, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Topper
authors.affiliation: Division of Medical Genetics, Akron Children's Hospital, One Perkins Square, Akron, OH 44308, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ward Melver
authors.affiliation: Division of Medical Genetics, Akron Children's Hospital, One Perkins Square, Akron, OH 44308, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stein
authors.affiliation: Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave, MC 0077, Chicago, IL 60637, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Reeder
authors.affiliation: Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave, MC 0077, Chicago, IL 60637, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Arndt
authors.affiliation: Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave, MC 0077, Chicago, IL 60637, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
mesh_terms: D018797:Cell Cycle Proteins; D002648:Child; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D044465:White People / Q000235:genetics
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins
keywords: CDK5RAP2; Next generation sequencing; Non-consanguineous; Primary autosomal recessive microcephaly