ACAN – spondyloepimetaphyseal dysplasia, aggrecan type

Aggrecan, encoded by ACAN, is a critical proteoglycan in cartilage extracellular matrix. Biallelic pathogenic variants in ACAN cause a severe autosomal recessive spondyloepimetaphyseal dysplasia, aggrecan type (MONDO:0013014) and are distinct from heterozygous mutations that underlie autosomal dominant skeletal disorders (PMID:29464738).

In a cohort of four unrelated Chinese families, whole-exome sequencing identified three novel ACAN variants in individuals with SEMD, aggrecan type. Segregation by Sanger sequencing confirmed biallelic inheritance in all probands (PMID:35261200).

A total of 4 probands exhibited growth retardation and characteristic metaphyseal abnormalities in each family (PMID:35261200).

Variant spectrum included one frameshift and two missense changes. The prototypical allele, c.1090dupG (p.Val364GlyfsTer4), introduces a premature stop codon leading to loss of the C-type lectin domain critical for aggrecan oligomerization and matrix assembly.

Functional assessment using conservation analysis and 3D protein modeling demonstrated that both missense substitutions (p.Glu983Gln; p.Trp2390Gly) disrupt domain stability and ligand-binding surfaces, and the frameshift variant undergoes nonsense-mediated decay (PMID:35261200).

The mechanism is consistent with recessive loss-of-function leading to deficient cartilage matrix integrity. No conflicting evidence has been reported for ACAN in recessive SEMD.

Together, genetic and in silico functional data support a ClinGen Moderate association between ACAN and spondyloepimetaphyseal dysplasia, aggrecan type. ACAN testing should be included in diagnostic gene panels for patients with severe short stature and metaphyseal dysplasia. Key take-home: Biallelic ACAN loss-of-function variants reliably predict autosomal recessive spondyloepimetaphyseal dysplasia, aggrecan type.

References

• 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
• Molecular genetics & genomic medicine • 2022 • Identification of variants in ACAN and PAPSS2 leading to spondyloepi(meta)physeal dysplasias in four Chinese families. PMID:35261200

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