Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of...

Area of Science:

• Genetics
• Medical Genetics
• Human Genetics

Background:

• Two male siblings presented with a complex phenotype including skeletal abnormalities (short humeri) and dysmorphic facial features (blepharophimosis).
• The newborn sibling also exhibited Hirschsprung disease, a congenital condition affecting the large intestine.
• Initial genetic investigations for known syndromes like Goldberg-Shprintzen and Ohdo syndrome (Say-Barber-Biesecker-Young-Simpson type) did not reveal mutations in KBP and KAT6B genes.

Observation:

• Two male siblings presented with short humeri, blepharophimosis, and other dysmorphic facial features.
• The newborn sibling was also diagnosed with Hirschsprung disease.
• Initial genetic testing for KBP and KAT6B genes did not reveal causative mutations.

Findings:

• Direct sequencing identified a missense mutation (c.3443G>A, p.Arg1148His) in the MED12 gene in both affected siblings.
• This mutation was inherited from their mother.
• The identified mutation expands the known mutational spectrum of the MED12 gene.

Implications:

• This discovery broadens the understanding of MED12-related disorders and their phenotypic variability.
• Accurate genetic diagnosis of MED12 mutations can aid in clinical management and genetic counseling.
• Further research into MED12 function may elucidate its role in developmental processes.