Primary Microcephaly, Autosomal Recessive, Panel

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that results from hypoplasia of the cerebral cortex. The hallmark clinical feature of MCPH is a head circumference at least three standard deviations below the population mean for age and sex (Jackson et al. 1998. PubMed ID: 9683597). In MCPH patients, microcephaly is usually detectable by the 32^nd week of gestation and is apparent at birth (Woods et al. 2005. PubMed ID: 15806441). 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. PubMed ID: 12046007; Passemard et al. 2009. PubMed ID: 19770472; Nicholas et al. 2010. PubMed ID: 20890279; Yu et al. 2010. PubMed ID: 20890278; Bacino et al. 2012. PubMed ID: 22308068). MCPH is panethnic. However, its incidence is variable and ranges from 1 in 30,000 to 1 in 250,000 living births (Komai et al. 1955. PubMed ID: 14361394; Verloes et al. 2013. PubMed ID: 20301772). Incidence is highest in populations where consanguineous marriages are broadly practiced (Bundey and Alam. 1993. PubMed ID: 8044647).

Autosomal recessive primary microcephaly is a genetically heterogeneous disorder. Ten genes have been implicated in the disorder: ASPM, WDR62, MCPH1, CEP152, CENPJ, STIL, CDK5RAP2, CEP135, KNL1 and CIT (Bond et al. 2002. PubMed ID: 12355089; Bilgüvar et al. 2010. PubMed ID: 20729831; Jackson et al. 2002. PubMed ID: 12046007; Guernsey et al. 2010. PubMed ID: 20598275; Bond et al. 2005. PubMed ID: 15793586; Kumar et al. 2009. PubMed ID: 19215732; Hussain et al. 2012. PubMed ID: 22521416; Li et al. 2016. PubMed ID: 27453578; Genin et al. 2012. PubMed ID: 22983954). To date, over 270 causative variants have been reported. ASPM pathogenic variants are the major cause of MCPH and account for up to 54% of cases with known pathogenic variants (Bond et al. 2003. PubMed ID: 14574646). WDR62 and MCPH1 pathogenic variants are the second most common cause (Nicholas et al. 2010. PubMed ID: 20890279). Pathogenic variants in the remaining genes appear to be rare and account for less than 5% each (Verloes et al. 2013. GeneReviews PMID: 20301772).

The vast majority of pathogenic variants are predicted to result in truncated proteins and include substitutions leading to premature stop codons, small deletions/insertions, and splicing variants. Large deletions were reported only in the MCPH1, ASPM and WDR62 genes. Although rare, missense variants and complex rearrangements have been documented. See individual gene test descriptions for information on molecular biology of gene products.

Sensitivity corresponds to the percentage of all cases with known disease-causing variants (Verloes et al. 2013. PMID: 20301772).

*Li et al. 2016. PubMed ID: 27453578

Pathogenic large copy number variations have been reported only in three genes included in this panel: MCPH1, ASPM, and WDR62.

MCPH1 deletions were identified in about 3% of patients with autosomal recessive primary microcephaly (Darvish et al. 2010. PubMed ID: 20978018). To date, only one and two large deletions have been reported in the WDR62 and ASPM genes, respectively (Wang et al. 2017. PubMed ID: 27784895; Nicholas et al. 2009. PubMed ID: 19028728; Passemard et al. 2009. PubMed ID: 19770472).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes 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 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).