Primary Microcephaly, Autosomal Recessive, via the CEP152 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. 1998). In MCPH patients, microcephaly is usually detectable by the 32nd week of gestation and is apparent at birth (Woods et al. 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. 2002; Passemard et al. 2009; Nicholas et al. 2010; Yu et al. 2010; Bacino et al. 2012). MCPH is panethnic. However, its incidence is variable and ranges from 1 in 30,000 to 1 in 250,000 living births (Verloes et al. 2009). Incidence is highest in populations where consanguineous marriages are broadly practiced (Bundey and Alam 1993).

Autosomal recessive primary microcephaly is a genetically heterogeneous disorder. Several genes have been implicated in the disorder. These include: MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6 (Faheem et al. 2015; Bond et al. 2002; Bilgüvar et al. 2010; Jackson et al. 2002; Guernsey et al. 2010; Bond et al. 2005; Kumar et al. 2009; Hussain et al. 2012).

CEP152 pathogenic variants appear to be a rare cause of MCPH. To date, only three pathogenic variants were reported in families from a Maritime Canadian subpopulation and Pakistan (Guernsey et al. 2010; Sajid Hussain et al. 2013). They include one missense and two truncating variants. Complex rearrangements or large pathogenic deletions have not been reported to date (Human Gene Mutation Database).

CEP152 codes for a centrosomal protein that is involved in microtubules organization and cell division (Andersen et al. 2003)

CEP152 pathogenic variants appear to be a rare cause of autosomal recessive primary microcephaly. To date, only three variants were reported in four families from a Maritime Canadian subpopulation and from Pakistan (Guernsey et al. 2010; Hussain et al. 2013).

No large deletions or duplications have been reported to date in CEP152 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CEP152 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).