Microcephaly 2, Primary, Autosomal Recessive, With Or Without Cortical Malformations

A number sign (#) is used with this entry because primary microcephaly-2 (MCPH2) with or without cortical malformations is caused by homozygous or compound heterozygous mutation in the WDR62 gene (613583) on chromosome 19q13.

Description

Microcephaly-2 with or without cortical malformations is an autosomal recessive neurodevelopmental disorder showing phenotypic variability. Classically, primary microcephaly is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations (SD) below the age- and sex-matched population mean, and mental retardation with no other associated malformations and with no apparent etiology (Hofman, 1984). Patients with WDR62 mutations have head circumferences ranging from low-normal to severe (-9.8 SD), and most patients with brain scans have shown various types of cortical malformations. All have delayed psychomotor development; seizures are variable (summary by Yu et al., 2010).

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

Clinical Features

Roberts et al. (1999) reported 2 unrelated consanguineous Pakistani families with primary microcephaly (SD, -4 to -7 below normal) noted at birth, mild to moderate mental retardation, normal motor development, and no significant dysmorphic features. All parents were unaffected. Detailed neuroimaging was not performed.

Darvish et al. (2010) reported a consanguineous Iranian family with primary microcephaly who showed linkage to the MPCH2 locus. The 3 affected individuals also showed intrauterine growth retardation and facial dysmorphism, including broad nasal bridge, long philtrum, micrognathia, and thick lower lip.

Nicholas et al. (2010) reported 7 consanguineous families, 5 of Pakistani origin, with primary microcephaly, including the 2 families previously reported by Roberts et al. (1999). Affected children from 6 of the families had microcephaly apparent at birth or in the first months of life. Head circumferences ranged from -4 to -7 SD below normal. None had malformations or congenital anomalies, and none were dysmorphic, except for sloping forehead and disproportionate face and ears compared to the skull. None had seizures. All had mild to moderate nonprogressive mental retardation and delayed speech acquisition. All parents were unaffected. Brain imaging available from 1 affected child showed a simplified gyral pattern. The seventh child, a girl, had a more severe phenotype with severe mental retardation, head circumference of -5 SD, and simplified gyral pattern and thickened cortex on brain MRI. At age 10 years, she used gestures and pictures to communicate simple needs, and was incontinent and socially withdrawn. She had no other neurologic or dysmorphic features and no seizures.

Bilguvar et al. (2010) described 10 patients, the product of consanguineous Turkish unions, manifesting with microcephaly, moderate to severe mental retardation, and cortical malformations including pachygyria with cortical thickening, microgyria, lissencephaly, hypoplasia of the corpus callosum, schizencephaly, and, in 1 instance, cerebellar hypoplasia. Some patients had seizures.

Yu et al. (2010) reported 6 consanguineous families in which affected offspring had microcephaly, severe developmental delay, and variable seizures. Most had lack of speech development, and some had lack of motor development. Some had spastic quadriparesis. Brain MRI showed small brains, markedly simplified gyral patterns, and corpus callosal abnormalities, as well as a diversity of additional cortical malformations including polymicrogyria, schizencephaly, and subcortical heterotopia, sometimes with asymmetry in the same brain. The cerebellum and brainstem were relatively spared in all patients. Postmortem examination of an affected 27-week-old fetus showed a profoundly small brain and smooth hemispheric surface with poorly defined Sylvian fissures and few sulci. The cerebral cortex was severely abnormal with thin layers and heterotopia. The findings indicated impaired neurogenesis with defects in proliferation and neuronal migration.

Bhat et al. (2011) reported 2 unrelated consanguineous Indian families with MCPH2 with cortical malformations. The patients ranged in age from 5 to 11 years, and head circumferences were between -4 and -9 SD. All had developmental delay with variable degrees of mental retardation. Brain MRI showed variable changes, including pachygyria, dysplastic cortex, widened sulci, polymicrogyria, microlissencephaly, and band heterotopia.

Murdock et al. (2011) reported 2 brothers, born of unrelated parents of northern European descent, with variable severity of MCHP2 with polymicrogyria. The first sib, whose pregnancy was complicated by gestational diabetes, had a more severe phenotype, with extensive bilateral polymicrogyria, abnormal corpus callosum, global developmental delay, intractable seizures, and spastic quadriparesis. The second sib, with extensive polymicrogyria and gray matter heterotopia but no seizures, had age-appropriate cognition at age 7 years and only mild unilateral hemiparesis. Both patients had head circumferences less than the fifth percentile.

Mapping

Roberts et al. (1999) demonstrated genetic heterogeneity in primary microcephaly by identifying a second locus on chromosome 19q13.1-q13.2 in 2 multiaffected consanguineous families. The minimum critical region containing the MCPH2 locus was defined by the polymorphic markers D19S416 and D19S420, spanning a region of approximately 7.6 cM.

By homozygosity mapping of 112 consanguineous Iranian families with primary microcephaly, Darvish et al. (2010) identified 3 families with primary microcephaly that showed linkage to the MPCH2 locus.

Molecular Genetics

In affected members of 2 consanguineous Pakistani families with primary microcephaly, previously reported by Roberts et al. (1999), Nicholas et al. (2010) identified 2 different homozygous mutations in the WDR62 gene (R438H; 613583.0006 and 4241dupT; 613583.0007, respectively). In 5 additional consanguineous families of Pakistani, Arab, and Caucasian ancestry with primary microcephaly, they identified 4 different homozygous WDR62 mutations (see, e.g., 613583.0008-613583.0009, 613583.0011).

Bilguvar et al. (2010) reported 2 missense, 2 nonsense, and 2 frameshift mutations in the WDR62 gene (see, e.g., 613583.0001-613583.0005) in 10 patients with microcephaly, cortical malformations, and mental retardation.

Yu et al. (2010) identified 6 different homozygous mutations in the WDR62 gene (see, e.g., 613583.0009-613583.0011) in affected members of 6 consanguineous families with microcephaly-2 with cortical malformations, including polymicrogyria, schizencephaly, and subcortical heterotopia.

Bhat et al. (2011) identified 2 different homozygous truncating WDR62 mutations in 2 unrelated consanguineous Indian families with MCPH2 with cortical malformations, bringing the total number of pathogenic mutations in the gene to 17. Six of the 17 mutations are missense, and mutations occurred throughout the gene sequence. Bhat et al. (2011) emphasized the wide phenotypic spectrum of cortical malformations in mutation carriers.

Murdock et al. (2011) reported 2 brothers, born of unrelated parents of northern European descent, with variable severity of MCHP2 with polymicrogyria. Exome sequencing identified compound heterozygosity for 2 truncating mutations in the WDR62 gene (613583.0012 and 613583.0013).

Sajid Hussain et al. (2013) found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. ASPM (605481) was the most commonly mutated gene, consistent with MCPH5 (608716), followed by WDR62. Linkage to the WDR62 gene was found in 7 families, but WDR62 mutations were only found in 5 families.