Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

Abstract

Purpose We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Methods We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. Results In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. Conclusion We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex

“…It is likely that some of the primary roles that Pcdhγc4 has in the adjustment of cIN cell number to match the number of excitatory neurons apply also to the human cerebral cortex. Recent work suggests that Pcdhγc4 plays a critical role in human brain development as mutations in this gene are associated with a neurodevelopmental syndrome with progressive microcephaly and seizures (Iqbal et al, 2021). An understanding of the cell-cell interactions that use Pcdhγc4 to regulate cIN cell death should give fundamental insights into how the cerebral cortex forms and evolves.…”

Gaps in the phenotype descriptions of ultra-rare genetic conditions: review and multicenter consensus reporting guidelines

“…The overall qualitative assessment of reporting was deemed “superficial/deficient” or “absent” in 87% (Domain I: Development, cognition, and mental health) to 98% (Domain IV: Pain, sleep, and quality of life) of papers (Figure 1). Five (2.5% of 200) reports were deemed “strong” in any single domain (pertaining to the genetic conditions associated with variants in the genes ADARB1 33 , GNAI1 34 , NCAPG2 35 , PCDHGC4 36 , and SPTBN1 37 ). No reports were deemed “strong” in their reporting across each of Domains I-IV.…”

How clustered protocadherin binding specificity is tuned for neuronal self-/nonself-recognition

“…Moreover, Garrett et al discovered that neuronal survival and postnatal viability are controlled solely by γC4 suggesting a function that is unique to this isoform (although it presumably requires β and/or other γ carriers to reach the cell surface) ( Garrett et al, 2019 ). Additionally, a recent paper by Iqbal et al has shown that genetic γC4 variants cause a neurodevelopmental disorder which is potentially linked to γC4’s role in programmed cell death of neuronal cells ( Iqbal et al, 2021 ). Below we report extensive biophysical interaction studies of C-type isoform ectodomains and report the first crystal structure of a trans dimer formed by γC4.…”