CLTC as a clinically novel gene associated with multiple malformations and developmental delay

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Diagnostic exome sequencing is crucial for unexplained dysmorphism and developmental delay.
• Traditional genetic testing failed to identify the molecular cause in this patient.
• The patient presented with severe neonatal issues, global developmental delays, dysmorphic features, and neuroblastoma.

Purpose of the Study:

• To determine the molecular etiology of unexplained developmental delay and dysmorphism in a pediatric patient.
• To identify novel genetic variants associated with complex congenital anomalies.

Main Methods:

• Whole-exome sequencing (WES) was performed.
• Bioinformatic filtering and expert medical review were utilized to analyze WES data.
• Karyotype and oligo-microarray analyses were conducted and yielded normal results.

Main Results:

• WES identified a heterozygous de novo frameshift mutation (c.2737_2738dupGA p.D913Efs*59) in the CLTC gene.
• This mutation affects Clathrin Heavy Chain 1 (CHC1), a protein vital for brain function and placental development.
• The identified CLTC alteration provides a likely molecular explanation for the patient's phenotype.

Conclusions:

• The identified CLTC mutation is strongly associated with the patient's complex phenotype, including developmental delays and dysmorphism.
• CHC1 plays a critical role in neurological development and function.
• Further functional studies are warranted to elucidate the precise impact of this CLTC alteration on CHC1 function and human disease.