A brother and sister of consanguineous Middle Eastern ancestry were seen in the neurogenetics clinic at the University of Chicago with a rare congenital microcephaly syndrome characterized by microcephaly with asymmetrical polymicrogyria (PMG) and severe developmental handicap.
Both children had small head sizes (or MIC) at birth following unremarkable pregnancies. Their birth occipitofrontal circumferences (OFC) were -2 to -3 standard deviations (SD) below the mean and progressed later to -6 SD below the mean. Both have significant developmental handicap. The older brother sat at 1 year of age, stood with assistance at 2 years. At 9 years of age, he was able to take a few steps with assistance, makes a few noises but is non-verbal. The younger sister was profoundly affected as well. She was non-ambulatory and non-verbal.
Physical examination was remarkable for marked microcephaly with a low forehead, but no other dysmorphic features. Neurologic examination revealed profound developmental handicap, with inability to walk, decreased muscle bulk, diffuse mild hypotonia and brisk reflexes.
Their brain MRI showed moderate to severe microcephaly, with a simplified gyral pattern, enlarged extra-axial space, and a diffusely irregular gyral surface consistent with polymicrogyria (PMG).
Both children were found to harbor a homozygous mutation (c.1588insT) in the WDR62 gene, one of the newest genes implicated in autosomal recessive primary microcephaly.
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a small sized brain. Several recessive genes underlying MCPH have been identified Although their encoded proteins serve diverse functions, evidence exists that most involve mitotic alterations during neuronal proliferation.
Clinically, MCPH is divided into two distinct groups. The first is composed of children with extreme MIC but only moderate neurologic problems, with mild-moderate developmental delay without spasticity or epilepsy. ~40% of MCPH cases are due to mutations in the ASPM gene. Other implicated genes in this group include CDK5RAP2, CENPJ, MCPH1 and STIL.
The second group consists of primary MIC with severe developmental handicap, and occasionally with additional brain malformations. Two recently identified genes in this group include PNKP and WDR62.
WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. Homozygous missense and frameshift mutations have been identified in seven consanguineous families with primary MIC. Additional brain MRI abnormalities include callosal abnormalities, cortical asymmetry and possible heterotopia. Therefore, WDR62 is believed to have a central role in neuronal proliferation and migration.
By: Ghayda Mirzaa, M.D., Clinical Molecular Genetics Fellow, The University of Chicago
References:
- Yu TW, Mochida GH, Tischfield DJ, et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nature Genetics, 2010;42:1015-1020.
- Nicholas AK, Khurshid M, Desir J, et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 2010;42:1010-4.
- Bilguvar K, Oztirk AK, Luovi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010 Sep 9;467(7312):207-10.