Identification of novel ACAN mutations in two Chinese families and genotype-phenotype correlation in patients with 74 pathogenic ACAN variations

Abstract

Background: ACAN (OMIM 155760) is located on chromosome 15q26 and encodes the production of aggrecan. Aggrecan is a large chondroitin sulfate proteoglycan with a molecular weight of 254 kDa and contains 2530 amino acids. It is a critical structural component of the extracellular matrix of cartilage, including growth plate, articular, and intervertebral disk cartilage. It plays a key role in bone development.

Methods: Here, we describe two pedigrees with loss-of-function variants in ACAN. Whole exome sequencing was performed for the probands from each family. We illustrate the clinical variability associated with ACAN variants.

Results: The proband of pedigree A manifested short stature, relative macrocephaly, mild flat nasal bridge, low-set ears, short neck, and short thumbs. The proband of pedigree B had short height, abnormal vertebral development, and central precocious puberty. By trio-based whole exome sequencing and in silico analyses, we identified two de novo heterozygous variants of ACAN: NM_013227.4: c.116dupT, p.Arg40Glufs*51 and NM_013227.4: c.2367delC, p.Ser790Glnfs*20 (accession number: AC103982.10).

Conclusion: The clinical manifestations of ACAN gene variants are diverse. ACAN gene variants are important genetic factors for short stature and should be considered as the differential diagnosis of children with idiopathic short stature (ISS).

FIGURE 1

Clinical presentation and genetic analysis of pedigree A. (a) The proband of pedigree A: the proband manifested relative macrocephaly, mild flat nasal bridge, low‐set ears, short neck, short thumbs, and pectus excavatum. (b) BA was 5 years and 6 months by x‐ray imaging of the left hand (Chronological age: 8 years and 8 months). (c) Pedigrees of the family: the proband and his mother, maternal grandfather had the same gene mutation. (d) The gene map of pedigree A: the proband (Ⅲ‐1) and his mother (Ⅱ‐2), maternal grandfather (Ⅰ‐1) had the same heterozygous frameshift mutation c.116dupT (p.Arg40Glufs*51) in exon 3 of the ACAN gene, while the father (Ⅱ‐1) was normal

FIGURE 2

Lateral radiograph of the proband and genetic analysis of pedigree B. (a) Lateral radiograph: the lumbar spine was slightly lateralized. The physiological curvature of the cervical spine became straight, cervical 4 and 5 were partially fused, and the intervertebral space between them was slightly narrow. (b) Pedigrees of the family: the proband and his mother had the same gene mutation. (c) The gene map of pedigree B: the proband and her mother had the same heterozygous frameshift mutation c.2367delC (p.Ser790Glnfs*20) in exon 12 of the ACAN gene, while the father was normal

FIGURE 3

The structure of ACAN, different phenotypes, and the proportion of mutation types and domains. (a) The structure of ACAN and the locations of pathogenic sequence variants. Structure of ACAN is shown in the upper row with exon numbers making in the blue blocks. Structure of the aggrecan protein is shown in the lower row with crucial domains drawing approximately to scale. (G, globular domain; IGD, interglobular domain; KS, keratan sulfate; CS, chondroitin sulfate; EGF, epidermal growth factor‐like domain; CLD, C‐type lectin domain; CRP, complement regulatory‐like domain). (b) Number of ACAN mutations with different phenotypes. (c) The proportion of ACAN mutation types. (d) The proportion of ACAN mutation domains