Case Report: Prenatal diagnosis and postnatal reclassification of a CNNM2 gene variant from variant of uncertain significance to likely pathogenic: a family report
Year: 2026
Type: article
Abstract: We report a family in which a maternally inherited heterozygous CNNM2 c.952T > C (p.Ser318Pro) variant was reclassified from a variant of uncertain significance (VUS) to Likely Pathogenic. The affected mother, a 25-year-old woman with moderate intellectual disability, psychomotor delay, seizures, bilateral strabismus, and hypomagnesemia, underwent medical exome sequencing to establish a molecular diagnosis. At initial detection, the variant was classified as a VUS (PM1 + PM2_Supporting+PP3; 4 points). Parental testing during the first pregnancy showed that both unaffected parents of the mother were wild-type, supporting an assumed de novo occurrence in the affected mother. Retrospective re-evaluation of the evidence available at that time—PM1 + PM2_Supporting+PM6 + PP3—yielded 6 points, already reaching the lower bound for Likely Pathogenic, although the contemporaneous prenatal reports conservatively retained the VUS classification. In two consecutive pregnancies, prenatal testing showed that each fetus was heterozygous for the variant; the first pregnancy was electively terminated, whereas the second was continued and resulted in the birth of the proband. At approximately 6 months of age, the proband developed hypotonia, hypomagnesemia, and delayed motor development, and cranial magnetic resonance imaging showed delayed myelination, cortical underdevelopment, and widened frontotemporal extra-axial spaces. Postnatal trio whole-exome sequencing confirmed maternal inheritance. Addition of segregation and phenotypic evidence supported a final classification of Likely Pathogenic (PM1 + PM2_Supporting+PM6 + PP1 + PP3; 7 points). Postnatal findings did not independently establish pathogenicity; rather, they added confirmatory evidence to family data that already warranted timely prenatal re-review. This case highlights the need for immediate re-evaluation of prenatally detected VUS when new segregation evidence becomes available.
Source: Frontiers in Medicine
Institution: Hainan Maternal and Child Health Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225643223