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FAM20B Related Skeletal Dysplasia: Expanding the Prenatal Phenotype
Arda Arduç1,2, Linda C Zuurbier3, Merel C van Maarle3
1Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Clinical Genetics
|November 24, 2025
Summary
Severe skeletal dysplasia in three fetuses was linked to novel variants in the FAM20B gene, which is crucial for proteoglycan biosynthesis and skeletal development.
Area of Science:
- Genetics
- Developmental Biology
- Biochemistry
Background:
- FAM20B encodes glycosaminoglycan xylosylkinase, an enzyme vital for proteoglycan synthesis.
- Pathogenic variants in FAM20B have been recently associated with skeletal dysplasia.
- Proteoglycans play a critical role in skeletal development and integrity.
Purpose of the Study:
- To report and characterize the prenatal phenotype of severe skeletal anomalies associated with biallelic FAM20B variants.
- To identify the genetic cause of severe skeletal dysplasia in three affected fetuses from a single family.
- To elucidate the functional impact of novel FAM20B variants on protein structure and function.
Main Methods:
- Clinical evaluation of three affected fetuses/infants with detailed prenatal and postnatal examinations.
- Genetic analysis including SNP-array and exome sequencing to identify causative variants.
- In silico protein modeling to assess the structural and functional consequences of the identified missense variant.
Main Results:
- Three fetuses presented with severe skeletal anomalies, including limb shortening, joint dislocations, intrauterine growth restriction, and craniofacial dysmorphisms.
- Genetic analysis revealed compound heterozygosity for a paternal deletion and a maternal missense variant (p.Arg290Cys) in FAM20B.
- In silico modeling indicated the p.Arg290Cys variant destabilizes FAM20B protein structure, impairing catalytic function due to loss of a critical salt bridge.
Conclusions:
- This study describes the severe prenatal phenotype of FAM20B-related skeletal dysplasia, expanding the known phenotypic spectrum.
- The findings underscore the essential role of FAM20B in early skeletal development.
- Novel FAM20B variants, including a deletion and a functionally significant missense mutation, can cause severe, often lethal, skeletal dysplasia.
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