Novel no-stop FLNA mutation causes multi-organ involvement in males

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Mutations in the Filamin A (FLNA) gene are known to cause X-linked periventricular nodular heterotopia (XL-PNH).
• XL-PNH-associated mutations are typically considered lethal in hemizygous males, with rare exceptions surviving infancy due to specific mutation types or somatic mosaicism.

Observation:

• Two brothers presented with failure to thrive, distinct facial features (hypertelorism), and systemic involvement.
• Affected individuals exhibited severe intestinal issues, congenital short bowel, periventricular nodular heterotopia, pyloric stenosis, wandering spleen, cardiac defects, and other anomalies.
• Genetic testing identified a novel FLNA no-stop mutation (c.7941_7942delCT, p.(*2648Serext*100)) in the affected males and their cousin.

Findings:

• The novel FLNA mutation, the most distal reported to date, resulted in diminished FLNA protein and mRNA levels in patient fibroblasts.
• In females, this mutation causes classical XL-PNH.
• In males, this distal FLNA mutation leads to an unusual and severe multi-organ phenotype, challenging the notion of lethality for all FLNA mutations in hemizygous males.

Implications:

• This study expands the spectrum of FLNA-associated phenotypes, particularly in males.
• The findings provide critical insights into genotype-phenotype correlations for FLNA mutations.
• Understanding these unusual presentations in males can inform diagnosis and management of complex congenital disorders.