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Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature.

ABSTRACT: Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of -3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.

SUBMITTER: Hauer NN

PROVIDER: S-EPMC5610314 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature.

Hauer Nadine N NN Sticht Heinrich H Boppudi Sangamitra S Büttner Christian C Kraus Cornelia C Trautmann Udo U Zenker Martin M Zweier Christiane C Wiesener Antje A Jamra Rami Abou RA Wieczorek Dagmar D Kelkel Jaqueline J Jung Anna-Maria AM Uebe Steffen S Ekici Arif B AB Rohrer Tilman T Reis André A Reis André A Dörr Helmuth-Günther HG Thiel Christian T CT

Scientific reports 20170922 1

Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiop ...[more]

PMID: 28939912

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Project description:BackgroundLinear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.Case presentationWe report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.ConclusionWe investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

Dataset Information

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature.

Publications

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature.

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