Microcephaly 22, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-22 (MCPH22) is caused by homozygous or compound heterozygous mutation in the NCAPD3 gene (609276) on chromosome 11q25.

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

Clinical Features

Martin et al. (2016) reported 2 unrelated boys with primary microcephaly. One patient (P2) was a 6-year-old boy with short stature (-5.7 SD) and microcephaly (-5.4 SD). He had normal development, but later developed a malignant anaplastic medulloblastoma resulting in death at age 11 years. The second patient (P4) was a 7-year-old boy with milder microcephaly (-2.7 SD), moderate developmental delay, seizures, and limb hypertonia.

Inheritance

The transmission pattern of MCPH22 in the families reported by Martin et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients (P2 and P4) with MCPH22, Martin et al. (2016) identified homozygous or compound heterozygous mutations in the NCAPD3 gene (609276.0001-609276.0003). The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the second patient was found by targeted sequencing. Both mutations segregated with the disorder in the families. P2, who had a frameshift and a splice site mutation, had a more severe phenotype than P4, who had a missense mutation. Fibroblasts from both patients showed impaired chromosome segregation and abnormal recovery from mitotic condensation compared to controls. In P2 cells, this was associated with increased numbers of mid- and late-anaphase cells, increased ultrafine DNA bridges, variably increased micronuclei, and increased aneuploidy, all indicating decatenation failure at mitosis. These abnormalities could potentially reduce neuronal cell proliferation, viability, and survival, resulting in microcephaly. The findings indicated that the mutations disrupted condensin-dependent mitotic chromosome integrity.

Animal Model

Martin et al. (2016) found that mice with a heterozygous or homozygous I15N mutation in the Ncaph2 gene (611230), which is part of the condensin II complex with NCAPD3, developed microcephaly with decreased brain weight, and reduced cortical surface compared to controls. These abnormalities, which were more severe in the homozygous than in the heterozygous mice, were associated with increased chromatin bridges during anaphase and impaired chromosomal segregation in apical neuronal progenitors compared to controls, resulting in decreased neuronal cell proliferation and survival. The mitotic spindle orientation was normal.