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J Hum Genet. 2017 Jul;62(7):717-721. doi: 10.1038/jhg.2017.33. Epub 2017 Mar 23.

Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation.

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Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Inoue Pediatric Clinic, Nagasaki, Japan.
Department of Orthopedic Surgery, Nagasaki University Hospital, Nagasaki, Japan.


Aggrecan is a critical proteoglycan component of the extracellular matrix of the growth plates and articular cartilage and has a key role in the biophysical and biomechanical properties of cartilage. Recently, heterozygous mutations in the ACAN gene, which encodes aggrecan, have been identified in patients with short stature and accelerated bone age. We herein report another family with a heterozygous ACAN mutation associated with idiopathic short stature along with accelerated bone age and early-onset herniation of the lumbar discs at the levels of L1/2 through L5/S1. Whole-exome sequencing identified a novel heterozygous frameshift mutation in the ACAN gene (c.1744delT; p.Phe582fs*69) in all of the affected family members but not in the unaffected one, providing further evidence that ACAN haploinsufficiency causes short stature with advanced bone maturation. In addition, we advocate early-onset multiple disc herniation as a novel phenotype associated with ACAN haploinsufficiency.

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