Primary microcephaly (MCPH) is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and mental retardation, with no other associated malformations and with no ... Primary microcephaly (MCPH) is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and mental retardation, with no other associated malformations and with no apparent etiology. Most cases of primary microcephaly show an autosomal recessive mode of inheritance (summary by Woods et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Jamieson et al. (1999) reported 4 sibs, born of consanguineous Moroccan parents, with primary microcephaly (head circumference -5 to -6 SD). The patients also had poor overall growth and mental retardation. Brain CT scan of the proband showed ... Jamieson et al. (1999) reported 4 sibs, born of consanguineous Moroccan parents, with primary microcephaly (head circumference -5 to -6 SD). The patients also had poor overall growth and mental retardation. Brain CT scan of the proband showed enlarged ventricles, but no other abnormalities. Genin et al. (2012) provided follow-up of the family reported by Jamieson et al. (1999) and reported 2 additional similarly affected families. All were consanguineous and of Moroccan origin from small villages about 50 km apart. All patients had head circumferences of -4 to -7 SD and mild to moderate mental retardation. Stature and motor development was normal; none had seizures or neurologic deficits.
By homozygosity mapping followed by candidate gene sequencing in 3 Moroccan families with primary microcephaly, including the family originally reported by Jamieson et al. (1999), Genin et al. (2012) identified a homozygous mutation in the CASC5 gene (609173.0001). ... By homozygosity mapping followed by candidate gene sequencing in 3 Moroccan families with primary microcephaly, including the family originally reported by Jamieson et al. (1999), Genin et al. (2012) identified a homozygous mutation in the CASC5 gene (609173.0001). None of the patients had a mutation in the CEP152 gene. Haplotype analysis indicated a founder effect. The mutation was predicted to inactivate an exonic splicing enhancer, and was demonstrated to result in abnormal splicing and production of a transcript lacking exon 18 and causing premature termination. However, normal CASC5 protein levels were also found in patient lymphoblastoid cells. Patient lymphoblasts showed no abnormalities in mitosis, no changes in growth rate, and no micronuclei. Immunofluorescence studies showed no defects of CASC5 expression in patient fibroblasts, and mitotic spindles were normal. None of the patients developed leukemia, consistent with normal CASC5 function in nonneurologic cells. Although this mutant CASC5 appeared to function normally in patient lymphoblasts and fibroblasts, Genin et al. (2012) speculated that it may express the defect only in neural cells. Genin et al. (2012) directly sequenced the CASC5 gene in a cohort of patients with primary microcephaly, including 3 probands from consanguineous families with homozygosity at the MCPH4 locus, and did not find any additional mutations, suggesting that CASC5 mutations are a rare cause of microcephaly.