Primary Microcephaly, Autosomal Recessive, via the ASPM 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. PubMed ID: 9683597; Verloes et al. 2013. PubMed ID: 20301772). In MCPH patients, microcephaly is usually detectable by the 32nd 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 pan ethnic. However, its incidence is variable and ranges from 1 in 30,000 to 1 in 250,000 living births (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).

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. 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). ASPM pathogenic variants are the most common cause of MCPH world-wide, accounting for up to 50% of cases with a molecular diagnosis (Verloes et al. 2013. PubMed ID: 20301772). About 100 pathogenic variants have been reported. The vast majority are predicted to result in truncated proteins and include substitutions, small frameshift deletions or insertions, and splicing variants. Although rare, complex rearrangements and large pathogenic deletions were also reported (Pichon et al. 2004. PubMed ID: 14997185; Nicholas et al. 2009. PubMed ID: 19028728; Verloes et al. 2013. PubMed ID: 20301772). To date, only two missense pathogenic variants, (c.5584A>C, p.Lys1862Gln) and (c.9539A>C, p.Gln3180Pro), were published (Darvish et al. 2010. PubMed ID: 20978018; Gul et al. 2006. PubMed ID: 16673149). ASPM pathogenic variants are generally associated with variable head circumference and mild to moderate mental retardation (Darvish et al. 2010. PubMed ID: 20978018).

ASPM encodes the abnormal spindle-like microcephaly-associated protein, which is involved in mitotic spindle function in embryonic neuroblasts (Bond et al. 2002. PubMed ID: 12355089).

Pathogenic ASPM variants are found in 25-50% of patients diagnosed with primary microcephaly, more than any other single gene cause, making this the most common form of this disorder (Verloes et al. 2013. PubMed ID: 20301772). Based on our NGS sequencing statistics and the types of known pathogenic variants previously reported in this gene, the analytical sensitivity (proportion of ASPM pathogenic variants detected by our sequencing methods) is expected to be very high.

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