STIL – Holoprosencephaly

STIL (SCL/TAL1 interrupting locus) is a core centriole duplication protein whose recessive mutations have been implicated in holoprosencephaly (Holoprosencephaly). Early brain cleavage defects in affected individuals underscore the role of STIL in forebrain patterning and midline formation.

Genetic evidence arises from two unrelated families: a consanguineous Turkish kindred with a homozygous missense variant c.2150G>A (p.Gly717Glu) segregating in two affected siblings (PMID:25658757), and a non-consanguineous prenatal case harboring compound heterozygous alleles c.2354_2355dupGA (p.Lys786GlufsTer4) and c.3838C>T (p.Arg1280Cys) identified postnatally in a fetus with holoprosencephaly features (PMID:24986681). Across these studies, three probands have presented with severe forebrain cleavage anomalies under an autosomal recessive inheritance model.

Segregation analysis supports pathogenicity, with one additional affected sibling demonstrating co-segregation of the homozygous p.Gly717Glu allele (PMID:25658757). The variant spectrum in holoprosencephaly cases includes missense and frameshift alleles, with c.2150G>A (p.Gly717Glu) serving as the archetypal HPE-causing change.

Functional assays confirm the deleterious impact of p.Gly717Glu: rescue experiments in U2OS cells show failure to restore centriole duplication upon depletion of endogenous STIL, and in situ hybridization in chick embryos demonstrates STIL expression concordant with early forebrain patterning (PMID:25658757). These data establish a loss-of-function mechanism underpinning holoprosencephaly.

No conflicting studies have disputed a recessive STIL-HPE association; all reports reproducibly link biallelic STIL disruption to midline brain malformations. While additional cohort studies may further refine variant prevalence, current evidence supports clinical testing of STIL in unexplained holoprosencephaly.

In summary, biallelic STIL mutations cause autosomal recessive holoprosencephaly via a loss-of-function mechanism, with functional rescue and expression data providing concordant support for pathogenicity. Key take-home: STIL should be included in diagnostic gene panels for early midline brain anomalies.

References

• Pediatric neurology • 2014 • A prenatal presentation of severe microcephaly and brain anomalies in a patient with novel compound heterozygous mutations in the STIL gene found postnatally with exome analysis. PMID:24986681
• PLoS One • 2015 • Homozygous STIL mutation causes holoprosencephaly and microcephaly in two siblings. PMID:25658757

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