Novel CLTC variants cause new brain and kidney phenotypes

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Heterozygous variants in the CLTC gene, encoding clathrin heavy chain, are linked to neurodevelopmental delay and associated features.
• The full spectrum of clinical manifestations for CLTC variants remains incompletely understood, with only 28 cases previously reported.

Observation:

• This study identifies three novel de novo CLTC variants (c.3662_3664del:p.(Leu1221del), c.2878T>C:p.(Trp960Arg), and c.2430+1G>T:p.(Glu769_Lys810del)) in three individuals.
• Individuals presented with previously unreported symptoms including brain abnormalities (cystic lesions), kidney issues (high-echogenicity, agenesis, reflux), respiratory problems (pneumonia), and hematological disorders (anemia, pancytopenia).
• One individual displayed prenatal abnormalities, including fetal growth restriction, brain lesions, echogenic kidneys, and a heart defect.

Findings:

• Novel CLTC variants contribute to a broader range of neurodevelopmental and systemic symptoms than previously recognized.
• Missense or small in-frame variants appear to correlate with more severe clinical presentations.
• The findings highlight the potential for CLTC variants to cause significant prenatal abnormalities affecting multiple organs.

Implications:

• These discoveries expand the phenotypic spectrum associated with CLTC variants, crucial for accurate genetic diagnosis.
• Considering CLTC variants in cases of unexplained neurodevelopmental delay and multiple congenital anomalies, especially prenatal findings, is recommended.
• Further research into CLTC function and variant effects can improve understanding and management of these rare disorders.