Christopher Tan, Melissa Dempsey, Soma Das

Primary Autosomal Recessive Microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly, mental retardation without other neurologic findings, and the absence of facial dysmorphism or other organ malformations. The most common gene implicated in MCPH is ASPM, with mutations accounting for approximately 40% of patients with a strict diagnosis of MCPH. A total of 86 mutations have been described in the ASPM gene to date that span the entire gene and the majority are predicted to result in protein truncation. A large percentage of mutations described have been homozygous and in consanguineous families primarily of East Asian and Middle Eastern origin.

Our molecular diagnostic laboratory has been offering full gene sequencing for ASPM since May 2009. We have studied 155 patient samples to date and have identified loss of function ASPM mutations in 22 probands. In total 27 different mutations were identified, including 24 novel mutations. Close to 50% of patients were compound heterozygotes, indicative of non-consanguinity in these patients. Ethnicity of patients ranged from Middle Eastern (36%), Caucasian (23%), Hispanic (23%), African (9%), African American (4%) and Mixed (4%). Clinical information was obtained for 15 of the patients with ASPM mutations and preliminary observations demonstrate severe microcephaly (less than 2 SD below mean at birth, and less than 3 SD below mean after age six months) for all patients with known information, cognitive delays in 6 patients, 2 of which were noted to be severe, motor delays in 8/15 patients, language delays in 5/15 patients and a simplified gyral pattern on brain MRI in 3 of 11 patients. Data will be presented on the mutations and additional sequence changes identified, several of which appear to be ethnic specific, as well as the corresponding clinical phenotype in mutation positive and negative patients.

Our experiences contribute towards the growing amount of genotype-phenotype data on ASPM-related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations.

This poster (#427) will be presented by Chris Tan Friday March 17: 10:30-11:30am.  Stop by and learn more about our experience with ASPM.