Primary Microcephaly, Autosomal Recessive, via the WDR62 Gene

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that results from hypoplasia of the cerebral cortex. The hallmark clinical feature of MCPH is head circumference at least three standard deviations below the population mean for age and sex (Jackson et al. Am J Hum Genet 63:541-546, 1998; Passemard et al. GeneReviews, 2009, www.genetests.org). In MCPH patients, microcephaly is usually detectable by the 32nd week of gestation and is apparent at birth (Woods et al. Am J Hum Genet 76:717-728, 2005). Typically, microcephaly persists throughout the patient’s lifetime. Additional features often include a sloping forehead, various degrees of cognitive disabilities, seizures, congenital hearing loss, and short stature. Brain imaging findings may include reduction of the cerebral cortical volume with simplification of the gyral cortical pattern, pachygyria with cortical thickening, lissencephaly, and polymicrogyria (Jackson et al. Am J Hum Genet 71:136-142, 2002; Passemard et al. Neurology 73:962-969, 2009; Nicholas et al. Nat Genet 42:1010-1014, 2010; Yu et al. Nat Genet 42:1015-1020, 2010; Bacino et al. Am J Med Genet A 158A:622-625, 2012). MCPH is panethnic. However, its incidence is variable and ranges from 1 in 30,000-250,000 live births (Passemard et al. GeneReviews, 2009, www.genetests.org). Incidence is highest in populations where consanguineous marriages are broadly practiced (Bundey and Alam. Eur J Hum Genet 1:206-219, 1993).

MCPH is a genetically heterogeneous disorder. To date, eight genes (ASPM, WDR62, MCPH1, CEP152, CENPJ, STIL, CDK5RAP2, and CEP135) have been implicated in the disorder (Bond et al. Nat Genet 32:316-320, 2002; Bilgüvar et al. Nature 467:207-210, 2010; Jackson, 2002; Guernsey et al. Am J Hum Genet 87:40-51, 2010; Bond et al. Nat Genet 37:353–355, 2005; Kumar et al. Am J Hum Genet 84:286–290, 2009; Hussain et al. Am J Hum Genet 90:871-878, 2012).

WDR62 variants are the second most common cause of MCPH (Nicholas et al. Nat Genet 42:1010-1044, 2011). To date, about 25 variants have been reported. Approximately two-thirds of these are predicted to result in truncated proteins and consist of nonsense variants, small deletions or insertions, and splicing variants. The remaining are missense variants. No large deletions or complex rearrangements have been reported. Patients with WDR62 pathogenic variants present with a broad range of clinical manifestations including severe microcephaly and cerebral cortical malformations, pachygyria, hypoplasia of the corpus callosum and the cerebellar cortex, lissencephaly, schizencephaly, polymicrogyria, psychomotor developmental delay, and aggressive behavior (Yu et al. Nat Genet 42:1015-20, 2010; Bilgüvar, 2010; Nicholas, 2011; Bacino, 2012).

The WDR62 gene encodes the WD repeat-containing protein 62, a spindle pole protein that is speculated to be involved in the division of neural precursor cells (Bilgüvar, 2010).

WDR62 variants are the second most common cause of MCPH (Nicholas et al. Nat Genet 42:1010-1014, 2010).

This test provides full coverage of all coding exons of the WDR62 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).