STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• Holoprosencephaly is a congenital brain malformation with diverse genetic causes.
• Many holoprosencephaly cases lack a molecular diagnosis.
• STIL gene mutations are associated with primary microcephaly (MCPH7).

Purpose of the Study:

• To identify the genetic cause of microcephaly and holoprosencephaly in a consanguineous family.
• To investigate the role of STIL gene mutations in holoprosencephaly.

Main Methods:

• Whole-exome sequencing
• Segregation analysis in an affected family
• Phenotypic analysis of affected individuals

Main Results:

• A homozygous truncating mutation in the STIL gene was identified.
• This STIL mutation caused both severe autosomal recessive microcephaly and lobar holoprosencephaly.
• STIL mutations are now linked to holoprosencephaly, expanding its known phenotype.

Conclusions:

• Biallelic STIL mutations can cause holoprosencephaly, in addition to microcephaly.
• This discovery broadens the spectrum of STIL-associated disorders.
• Identifies STIL as a novel gene implicated in holoprosencephaly pathogenesis.