Submission Details

PCNT was first reported in relation to autosomal recessive microcephalic osteodysplastic primordial dwarfism, type II (MOPDII) in 2008 (Rauch et al., PMID: 18174396 and Griffith et al., PMID: 18157127). Microcephalic osteodysplastic primordial dwarfism type II is characterized by intrauterine growth retardation (IUGR), severe proportionate short stature, and microcephaly. Patients occasionally present with additional syndromic features, including heart defects (PMID: 29961235) and oligodontia (PMID: 31606423) in addition to the typical skeletal manifestations observed. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, microcephalic osteodysplastic primordial dwarfism, type II (OMIM:210720) and Seckel syndrome. Seven variants (nonsense, frameshift, and canonical splice site) that have been reported in five probands in four publications (PMIDs: 18174396, 26231886, 33460028, 35568357) are included in this curation meeting phenotypic criteria including IUGR, short stature, and microcephaly. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (if applicable). The mechanism of pathogenicity is reported to be loss of function. The curation for this gene-disease relationship did not include experimental evidence. In summary, there is definitive evidence supporting the relationship between PCNT and autosomal recessive microcephalic osteodysplastic primordial dwarfism, type II. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date July 21, 2023 (SOP Version 9) and reviewed by experts from the ClinGen Syndromic Disorders GCEP on August 27, 2024.