Microcephaly 7, Primary, Autosomal Recessive

A number sign (#) is used with this entry because primary microcephaly-7 (MCPH7) is caused by homozygous mutation in the STIL gene (181590) on chromosome 1p33.

For a phenotypic description and discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Clinical Features

Darvish et al. (2010) reported a consanguineous Iranian family in which 4 individuals had primary microcephaly and mental retardation. Other features in this family included short stature, strabismus, ataxia, and seizures. The authors also reported a second consanguineous Iranian family with primary microcephaly in 3 individuals and no additional features.

Papari et al. (2013) reported a large consanguineous kindred from the Bushehr province of Iran in which 7 individuals had primary microcephaly with mild intellectual disability.

Kakar et al. (2015) reported a highly consanguineous Pakistani family in which 12 individuals had severe microcephaly (up to -10 SD), developmental delay, and severe intellectual disability. Six patients were deceased. Physical examination of the living patients showed a small cranium with sloping forehead and prominent midface with apparently large nose. Detailed information on 3 patients revealed absent speech, no seizures, no cleft lip or palate, and no single central maxillary incisor. Brain imaging, performed on 2 patients, showed severe microcephaly with a foreshortened frontal lobe, very small frontal horns, and a severe diffuse simplified gyral pattern most severe frontally. In addition, the images showed signs of lobar holoprosencephaly, including continuity of the white matter and cortex over the genu of the corpus callosum and continuity of the right- and left-sided basal ganglia across the midline.

Inheritance

The transmission pattern of MCPH7 in the families reported by Darvish et al. (2010) was consistent with autosomal recessive inheritance.

Mapping

In 5 Indian families with primary microcephaly, Kumar et al. (2009) found linkage to a locus on chromosome 1p33-p32.3 (combined multipoint maximum lod score of 6.97 between markers D1S2797 and D1S417), which they designated MCPH7.

By homozygosity mapping, Darvish et al. (2010) found that 2 (2.2%) of 112 consanguineous Iranian families with primary microcephaly showed linkage to the MCPH7 region. However, no mutations in the STIL gene were found.

Molecular Genetics

Kumar et al. (2009) identified 3 different homozygous mutations in the STIL gene (181590.0001-181590.0003) in affected members of 4 Indian families with autosomal recessive primary microcephaly.

In affected members of a large consanguineous kindred from the Bushehr province of Iran with primary microcephaly, Papari et al. (2013) identified a homozygous mutation in the STIL gene (L798W; 181590.0004). The mutation was found by linkage analysis and candidate gene sequencing. This family was ascertained from a larger cohort of 14 families from the same region in Iran with autosomal recessive primary microcephaly. One additional family had a mutation in the ASPM gene (605481), consistent with MCPH5 (608716), but no mutations were found in the other 12 families.

In affected members of a highly consanguineous Pakistani family with MCPH7, Kakar et al. (2015) identified a homozygous truncating mutation in the STIL gene (181590.0005). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family.