[Prenatal phenotype and genetic analysis of two fetuses with Osteocraniostenosis due to variants of FAM111A gene].

Abstract

Objective: To investigate the prenatal manifestation and genetic basis for two fetuses suspected for Osteocraniostenosis (OCS).

Methods: Two fetuses undergoing invasive prenatal diagnosis at Cangzhou People's Hospital in April and August 2021 for short long bones and abnormal skull morphology were selected as the study subjects. Clinical data were collected and analyzed. Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the two couples. Candidate variants were validated by Sanger sequencing. Literature was retrieved from CNKI, Wanfang Data Knowledge Service Platform and PubMed using keywords including "FAM111A gene", "gracile bone dysplasia", "FAM111A" and "osteocraniostenosis" from January 1, 2000 to June 30, 2025. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: K2020-049).

Results: Fetus 1 was found to have short limbs, abnormal skull morphology and shallow cerebral sulci. Fetus 2 showed short limbs, irregular skull halo, prominent forehead and bilateral frontal narrowing. Trio-WES revealed that fetus 1 has carried a heterozygous missense variant c.1582G>C (p.Asp528His) in exon 4 of the FAM111A gene, which was unreported previously. Fetus 2 has harbored a heterozygous in-frame deletion c.1020_1022delTTC (p.Ser343del) in exon 6 of the FAM111A gene, which has been recorded as likely pathogenic by the ClinVar and HGMD databases. Sanger sequencing confirmed that the parents of both fetuses were wild-type for the variant sites. A total of 9 previously reported patients with FAM111A-related gracile bone dysplasia/OCS from 4 publications were retrieved. The main clinical features included intrauterine growth restriction, hypomineralized skull, gracile long bones with narrow medullary cavities and characteristic facial anomalies, which were in large in keeping with the prenatal features of the two fetuses.

Conclusion: Both fetuses were diagnosed with FAM111A-related OCS based on the characteristic prenatal findings and identification of the FAM111A variants. Above finding expanded the phenotypic spectrum of FAM111A-associated disorders and provided clues for the prenatal diagnosis and genetic counseling.