Titel: Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies
ID: W2-006
Art: Invited talk
Redezeit: 15 min
Session: Workshop 2
Neurodevelopmental Disorders

Referent: Gökhan Yigit (Göttingen/DE)

Abstract - Text


Clustered protocadherins (cPCDH) are transmembrane proteins that constitute the largest subgroup within in the cadherin superfamily of cell-surface receptors. cPCDHs are widely, but differentially, expressed in the developing and mature vertebrate nervous system, and they provide neuronal cells with distinct and unique "barcodes" that form a molecular basis for self-nonself discrimination and neurite self-avoidance during neural circuit assembly. cPCDH are involved in different neurodevelopmental processes including neuronal survival, targeting of axons, dendrite arborization, and synaptic development. However, no Mendelian disorder has yet been directly linked to mutations in a member of the cPCHD family. Here, we report bi-allelic pathogenetic variants (three missense, five truncating) in Protocadherin-gamma-C4 (PCDHGC4) in 19 individuals from nine independent families who presented with a novel neurodevelopmental syndrome with progressive microcephaly, short stature, seizures, intellectual disability, and additional dysmorphic features. The five truncating variants are predicted to induce early protein truncation most like leading to complete loss of protein function. Three missense variants are located in extracellular cadherin (EC) domains EC5 and EC6, affecting evolutionary highly conserved amino acid residues, and using three-dimensional molecular modelling we could show that two of the identified exchanges influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influences the cis-dimerization interface of PCDHGC4. In conclusion, our findings indicate that bi-allelic, pathogenic variants in PCDHGC4 are causative of a novel autosomal recessive neurodevelopmental disorder, which, to the best of our knowledge, is the first time a member of the cPCDH family has been linked to a Mendelian disorder in humans.