ACAN – spondyloepiphyseal dysplasia, Kimberley type

Aggrecan (ACAN) is a key cartilage extracellular matrix proteoglycan, and heterozygous mutations cause autosomal dominant spondyloepiphyseal dysplasia, Kimberley type (SEDK) characterized by short stature and mild epiphyseal anomalies. The association between ACAN and SEDK is supported by multiple pedigrees and case series demonstrating consistent phenotype–genotype concordance and variant segregation. ACAN and spondyloepiphyseal dysplasia, Kimberley type form a clinically actionable gene–disease pair.

A 2022 case report described a 2-year-old male with symmetrical short stature harboring a heterozygous nonsense variant c.871C>T (p.Gln291Ter) segregating in the father and grandmother across three generations (3 affected relatives) (PMID:35434101). This novel truncating mutation expands the ACAN mutation spectrum and confirms autosomal dominant inheritance in SEDK.

In a cohort of 16 unrelated probands, heterozygous ACAN variants were identified in all cases, including two individuals with SEDK and 14 with short stature and brachydactyly (16 probands) (PMID:29464738). Six variants in this study were classified as pathogenic, including nonsense and frameshift alleles, and all segregated with the SEDK phenotype in multiplex families, underscoring genetic heterogeneity and allelic diversity.

The variant spectrum in SEDK comprises mainly loss-of-function alleles—nonsense, frameshift, and canonical splice site mutations—distributed across ACAN. c.871C>T (p.Gln291Ter) exemplifies a recurrent mechanism, while additional pathogenic variants like c.1608C>A (p.Tyr536Ter) further illustrate truncation-induced haploinsufficiency.

Functional studies on ACAN missense variants in the G3 domain demonstrate reduced secretion and impaired extracellular matrix ligand binding, supporting a haploinsufficiency mechanism for SEDK (PMID:35338222). Regulatory assays also show that ACAN expression is directly modulated by SHOX2 and SOX transcription factors, linking variant impact to disrupted cartilage homeostasis.

Collectively, genetic and functional data establish a Moderate ClinGen level of confidence for ACAN–SEDK association with clear autosomal dominant inheritance, segregation in multiple families, and mechanistic support. ACAN variant testing should be integrated into the diagnostic workup for short stature with epiphyseal anomalies. Key Take-home: Heterozygous ACAN truncating mutations reliably predict autosomal dominant spondyloepiphyseal dysplasia, Kimberley type, guiding genetic diagnosis and family counseling.

References

• World journal of clinical cases • 2022 • Short stature associated with a novel mutation in the aggrecan gene: A case report and literature review. PMID:35434101
• Clinical endocrinology • 2018 • Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature. PMID:29464738
• Scientific reports • 2022 • Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan. PMID:35338222

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