STIL – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced head circumference at birth, non-progressive cognitive impairment, and a smaller but architecturally normal brain cortex. STIL (SCL/TAL1 interrupting locus; HGNC:10879) encodes a core centriole duplication factor and was originally mapped as MCPH7 among twelve MCPH loci identified worldwide ([PMID:25951892]). Biallelic STIL mutations have since been implicated in severe fetal microcephaly with delayed cortical gyrification and corpus callosum dysgenesis, highlighting its crucial role in human neurogenesis ([PMID:29230157]).

STIL-related MCPH follows an autosomal recessive inheritance pattern, with affected individuals harboring compound heterozygous or homozygous variants leading to loss of STIL function. STIL appears on diagnostic panels alongside other centrosomal genes (e.g., MCPH1, WDR62, ASPM, CENPJ) across diverse populations, supporting its inclusion in routine genetic screening for MCPH ([PMID:25951892]; [PMID:21668957]). No recurrent or founder STIL alleles have been described to date.

Genetic segregation within a consanguineous family demonstrated two fetuses with severe microcephaly, delayed gyrification, and dysplastic corpus callosum, each inheriting compound heterozygous STIL mutations ([PMID:29230157]). This single-family study provides direct evidence for biallelic STIL variants in MCPH, with two affected fetuses showing complete cosegregation of the alleles.

Functional assays corroborate STIL’s pathogenic mechanism via centriole dysregulation. M-phase–synchronized amniocytes from affected fetuses displayed elongation of centrioles, a novel phenotype distinct from depletion- or overexpression-induced centriole number defects ([PMID:29230157]). Computational modelling of the STIL missense variant c.724C>T (p.Arg242Cys) predicted disrupted interaction with CENPJ, implicating perturbed centriole assembly in microcephaly pathogenesis ([PMID:23772360]).

No conflicting reports have refuted STIL’s role in MCPH. Instead, successive studies in diverse cohorts reinforce STIL’s critical function in centrosome-mediated neurogenesis. Remaining gaps include precise genotype–phenotype correlations and variant-specific functional thresholds.

In summary, cumulative genetic and experimental evidence supports a Moderate clinical validity for STIL in autosomal recessive primary microcephaly. STIL should be included in diagnostic gene panels, enabling early molecular diagnosis, genetic counseling, and prenatal testing for affected families.

Key Take-home: Biallelic STIL mutations disrupt centriole length control, causing autosomal recessive primary microcephaly; STIL testing informs early diagnosis and familial counseling.

References

• BMC medical genomics • 2015 • Molecular genetics of human primary microcephaly: an overview. PMID:25951892
• Molecular syndromology • 2017 • Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening. PMID:29230157
• Orphanet journal of rare diseases • 2011 • Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. PMID:21668957
• FEBS open bio • 2012 • In silico prediction of a disease-associated STIL mutant and its affect on the recruitment of centromere protein J (CENPJ). PMID:23772360

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