Pathogenic variant in NFIX gene affecting three sisters due to paternal mosaicism

Area of Science:

• Genetics
• Developmental Biology
• Clinical Medicine

Background:

• Familial cases of rare genetic syndromes often present diagnostic challenges.
• NFIX gene variants are associated with known developmental disorders like Marshall-Smith and Malan syndromes.
• Autosomal recessive inheritance is typically suspected in unaffected parents with affected offspring.

Observation:

• Three sisters presented with overlapping dysmorphic features including overgrowth, intellectual disability, macrocephaly, and scoliosis.
• Exome sequencing identified a heterozygous nonsense variant in the NFIX gene in all affected siblings.
• The father exhibited low-level (7%) mosaicism for the identified NFIX variant in his blood.

Findings:

• The identified NFIX variant in the siblings, coupled with paternal mosaicism, suggests a potential autosomal recessive inheritance pattern or a complex inheritance mechanism.
• Phenotypic overlap with NFIX-related disorders highlights the NFIX gene's critical role in neurodevelopment and craniofacial formation.
• This familial case expands the known phenotypic spectrum associated with NFIX variants.

Implications:

• Highlights the importance of investigating parental mosaicism in familial genetic disorders, even with seemingly unaffected parents.
• Underscores the need for comprehensive molecular analysis in diagnosing rare genetic syndromes with overlapping features.
• Contributes to understanding the genetic basis of developmental disorders and informs genetic counseling for affected families.