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      High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature

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          Abstract

          Context

          Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual.

          Objective

          To assess the frequency of pathogenic ACAN variants in selected individuals.

          Design

          The single-center cohort study was conducted at a tertiary university children’s hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype.

          Results

          Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (−0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy.

          Conclusions

          ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.

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          Most cited references34

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          Structure and function of aggrecan.

          Aggrecan is the major proteoglycan in the articular cartilage. This molecule is important in the proper functioning of articular cartilage because it provides a hydrated gel structure (via its interaction with hyaluronan and link protein) that endows the cartilage with load-bearing properties. It is also crucial in chondroskeletal morphogenesis during development. Aggrecan is a multimodular molecule expressed by chondrocytes. Its core protein is composed of three globular domains (G1, G2, and G3) and a large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein. This domain has the same structural motif as link protein. Functionally, the G1 domain interacts with hyaluronan acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.
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            The BoneXpert method for automated determination of skeletal maturity.

            Bone age rating is associated with a considerable variability from the human interpretation, and this is the motivation for presenting a new method for automated determination of bone age (skeletal maturity). The method, called BoneXpert, reconstructs, from radiographs of the hand, the borders of 15 bones automatically and then computes "intrinsic" bone ages for each of 13 bones (radius, ulna, and 11 short bones). Finally, it transforms the intrinsic bone ages into Greulich Pyle (GP) or Tanner Whitehouse (TW) bone age. The bone reconstruction method automatically rejects images with abnormal bone morphology or very poor image quality. From the methodological point of view, BoneXpert contains the following innovations: 1) a generative model (active appearance model) for the bone reconstruction; 2) the prediction of bone age from shape, intensity, and texture scores derived from principal component analysis; 3) the consensus bone age concept that defines bone age of each bone as the best estimate of the bone age of the other bones in the hand; 4) a common bone age model for males and females; and 5) the unified modelling of TW and GP bone age. BoneXpert is developed on 1559 images. It is validated on the Greulich Pyle atlas in the age range 2-17 years yielding an SD of 0.42 years [0.37; 0.47] 95% conf, and on 84 clinical TW-rated images yielding an SD of 0.80 years [0.68; 0.93] 95% conf. The precision of the GP bone age determination (its ability to yield the same result on a repeated radiograph) is inferred under suitable assumptions from six longitudinal series of radiographs. The result is an SD on a single determination of 0.17 years [0.13; 0.21] 95% conf.
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              The LMS method for constructing normalized growth standards

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                Author and article information

                Journal
                Eur J Endocrinol
                Eur. J. Endocrinol
                EJE
                European Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                0804-4643
                1479-683X
                March 2020
                13 December 2019
                : 182
                : 3
                : 243-253
                Affiliations
                [1 ]Unit for Special Laboratory Diagnostics , Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre, Ljubljana, Slovenia
                [2 ]Department of Pediatric Endocrinology , Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre, Ljubljana, Slovenia
                [3 ]Clinical Institute of Medical Genetics , University Medical Centre, Ljubljana, Slovenia
                [4 ]Faculty of Medicine , University of Ljubljana, Ljubljana, Slovenia
                Author notes
                Correspondence should be addressed to M Avbelj Stefanija; Email: magdalena.avbelj@ 123456mf.uni-lj.si
                Article
                EJE-19-0771
                10.1530/EJE-19-0771
                7087498
                31841439
                f4e8c430-d271-44f1-b970-01a81bf12edc
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 27 September 2019
                : 13 December 2019
                Categories
                Clinical Study

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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