A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34

Primary autosomal recessive microcephaly is a clinical diagnosis of exclusi on in an individual with a head circumference greater than or equal to 4 SD s below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebra l cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical p henotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineo us pedigree, using a whole-genome search, and have identified a third locus , MCPH3 at 9q34. The minimal critical region is similar to 12 cM, being def ined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD sc ore of 3.76 (recombination fraction 0) observed for the marker D9S290.