Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain...

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Primary autosomal recessive microcephaly (MCPH) is a group of developmental disorders characterized by prenatal onset of abnormal brain growth.
• MCPH can occur independently or as part of broader neurodevelopmental syndromes, sometimes involving cortical malformations and growth retardation.

Purpose of the Study:

• To identify the genetic cause of severe primary microcephaly, failure to thrive, congenital dermatitis, and developmental delay in a consanguineous Moroccan family.
• To investigate the role of the RTTN gene in a novel presentation of microcephalic primordial dwarfism with complex brain malformations.

Main Methods:

• Whole exome sequencing (WES) and Comparative Genomic Hybridization array were performed on affected siblings and family members.
• cDNA sequencing was used to analyze the splicing defects caused by the identified RTTN gene mutation.

Main Results:

• A novel homozygous missense variation (c.2953A>G;pArg985Gly) in the RTTN gene was identified in affected individuals.
• The mutation resulted in abnormal mRNA splicing, producing out-of-frame transcripts.
• Affected individuals presented with severe microcephaly, lissencephaly, periventricular heterotopia, failure to thrive, congenital dermatitis, and severe developmental delay.

Conclusions:

• A novel homozygous RTTN mutation is associated with a syndromic form of microcephalic primordial dwarfism, complex brain malformations, and congenital dermatitis.
• This discovery broadens the phenotypic spectrum of RTTN-associated disorders and highlights the role of RTTN in ciliary function and development.