Biallelic Variant in HAPLN1 is Associated With Skeletal Dysplasia With or Without Congenital Heart Disease

Hyaluronan and proteoglycan link protein 1 encodes HAPLN1, a critical structural protein in the extracellular matrix (ECM), essential for maintaining tissue architecture and integrity. HAPLN1 mediates stable interactions between hyaluronan and proteoglycans, crucial elements of the ECM that confer structural stability, elasticity, and functional regulation to connective tissues. Aberrations in HAPLN1 expression or function have been implicated in various pathological conditions, including inflammation and tumorigenesis in humans and skeletal dysplasias in mice. To the best of our knowledge, HAPLN1 has not been implicated in human skeletal dysplasia. Herein, we report a novel homozygous missense variant in HAPLN1 in four individuals from an extended consanguineous Kuwaiti family, co-segregating with a skeletal dysplasia phenotype. Affected individuals presented with shortened long bones of both upper and lower limbs, square-shaped iliac wings, narrowed sciatic notches, flattened acetabular roofs, progressive narrowing of the lumbar interpedicular distance with widened intervertebral disc spaces, and short, stubby metacarpal bones. Our findings identify HAPLN1 as a candidate gene underlying a newly described autosomal recessive skeletal dysplasia.