This poster (#0107) will be presented at the ACMG Annual Clinical Genetics Meeting by Chris Tan, our genetic counselor, Thursday March 21: 10:30am-11:30am.  Stop by and learn more

Primary Autosomal Recessive Microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly, intellectual disability without other neurologic findings, and the absence of facial dysmorphisms or other organ malformations. To date, 8 MCPH loci have been identified and their genetic causes include mutations in the genes encoding MCPH1(MCPH1, OMIM#251200), WDR62 (MCPH2, OMIM#613583), CDK5RAP2 (MCPH3, OMIM#604804), CEP152 (MCPH4, OMIM#613529), ASPM (MCPH5, OMIM#608716), CENPJ (MCPH6, OMIM#608393), STIL (MCPH7, OMIM#612703) and CEP135 (MCPH8, OMIM#614673). The incidence of MCPH appears to be less common in Caucasian populations than in Asian and Arab populations that practice consanguineous marriages.  Prevalence estimates range between 1 in a million in Caucasians up to 1/10,000 in Northern Pakistani populations. We describe the clinical and molecular investigations of a patient with primary microcephaly found to have heterozygous mutations identified in CDK5RAP2, only the fourth and fifth mutations to be described in this gene, the first in an individual that is not from a consanguineous family. 

The patient, a 6 year old female, was the product of a triplet pregnancy born at 33 weeks gestation.  She was noted, in utero, to have a smaller head than either of her sibs.  Upon physical exam at 5 years of age, her height and weight were below the third percentile and head circumference was below the first percentile.  The patient’s facial features were non-dysmorphic, and her chest, heart, lung, abdomen, back, genital and extremity exams were unremarkable.  Primary concern in the patient was her development, including delays in speech, retention, and recognition of numbers and letters.  The family is of Caucasian and Cherokee ancestry on the paternal side and Northern European ancestry on the maternal side. 

A next generation sequencing panel for genes involved in primary microcephaly was performed revealing two novel mutations in CDK5RAP2 (c.524_528delAGGCA and c.4005-1G>A), both of which were predicted to result in deleterious effects.  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 four Northern Pakistani and Somali consanguineous families.   Our patient represents the first non-consanguineous individual to have been identified with CDK5RAP2- related MCPH.  To date our laboratory has analyzed the CDK5RAP2 gene in 159 patients and data will also be presented on the additional sequence changes identified in this gene.  Our results highlight the utility of multi-gene sequencing panels to elucidate the etiology of genetically heterogeneous conditions.  Our experiences contribute towards the growing amount of data on CDK5RAP2-related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations.