Primary Microcephaly, Autosomal Recessive, via the STIL 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 pan ethnic. However, its incidence is variable and ranges from 1 in 30,000 to 1 in 250,000 living 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). STIL mutations appear to be a rare cause of MCPH. To date, only three pathogenic variants were reported in five families of Indian origin (Kumar, 2009). All mutations are predicted to result in truncated proteins and include one single nucleotide change, one splicing variant and one single nucleotide deletion. MCPH patients with STIL mutations that have been reported have reduced head circumference and various degrees of mental retardation. No other symptoms were detected (Kumar, 2009). STIL encodes the SCL/TAL1 interrupting locus, a cytosolic protein that has been involved in several cellular processes including microsomal functions (Kumar 2009).

This test will detect mutations in less than 5% of patients with a clinical diagnosis of primary microcephaly (Passemard et al. GeneReviews, 2009, www.genetests.org).

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