SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3(-/-) mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.Genetics of disease, diagnosis and treatmen

Genetic Predictors Of Long-term Response To Growth Hormone (gh) Therapy In Children With Gh Deficiency And Turner Syndrome: The Influence Of A Socs2 Polymorphism

Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47GHdeficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. CopyrightObjective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH).Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P=.016) and-202 A/C IGFBP3 (P=.013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001).Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS andGHDafter long-term rhGH therapy. Polymorphisms located inGHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.999E1808E1813Geffner, M.E., Dunger, D.B., Future directions: Growth prediction models (2007) Horm Res., 68, pp. 51-56Flores-Morales, A., Greenhalgh, C.J., Norstedt, G., Rico-Bautista, E., Negative regulation of growth hormone receptor signaling (2006) Mol Endocrinol., 20, pp. 241-253Greenhalgh, C.J., Rico-Bautista, E., Lorentzon, M., SOCS2 negatively regulates growth hormone action in vitro and in vivo (2005) J Clin Invest., 115, pp. 397-406Wassenaar, M.J., Dekkers, O.M., Pereira, A.M., Impact of the exon 3-deleted GH receptor polymorphism on baseline height and the growth response to recombinant human growth hormone therapy in growth hormone deficient(GHD)andnon-GHDchildren with short stature: A systematic review and meta-analysis (2009) J Clin Endocrinol Metab., 94, pp. 3721-3730Renehan, A.G., Solomon, M., Zwahlen, M., Growth hormone receptor polymorphism and growth hormone therapy response in children: A Bayesian meta-analysis (2012) AmJ Epidemiol., 175, pp. 867-877Costalonga, E.F., Antonini, S.R., Guerra-Junior, G., Mendonca, B.B., Arnhold, I.J., Jorge, A.A., The-202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency (2009) J Clin Endocrinol Metab., 94, pp. 588-595Braz, A.F., Costalonga, E.F., Montenegro, L.R., The interactive effect of GHR-exon 3 and-202 A/C IGFBP3 polymorphisms on rhGH responsiveness and treatment outcomes in patients with Turner syndrome (2012) J Clin Endocrinol Metab., 97, pp. E671-E677Weedon, M.N., Lango, H., Lindgren, C.M., Genome-wide association analysis identifies 20 loci that influence adult height (2008) Nat Genet., 40, pp. 575-583Gudbjartsson, D.F., Walters, G.B., Thorleifsson, G., Manysequence variants affecting diversity of adult human height (2008) Nat Genet., 40, pp. 609-615Chan, Y., Holmen, O.L., Dauber, A., Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals (2011) PLoS Genet., 7, p. e1002439Lou, X.Y., Chen, G.B., Yan, L., A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence (2007) Am J Hum Genet., 80, pp. 1125-1137Lango Allen, H., Estrada, K., Lettre, G., Hundreds of variants clustered in genomic loci and biological pathways affect human height (2010) Nature., 467, pp. 832-838Lanktree, M.B., Guo, Y., Murtaza, M., Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height (2011) Am J Hum Genet., 88, pp. 6-18Ranke, M.B., Lindberg, A., Albertsson-Wikland, K., Wilton, P., Price, D.A., Reiter, E.O., Increased response, but lower responsiveness, to growth hormone (GH) in very young children (aged 0-3 years) with idiopathicGHDeficiency: Analysis of data from KIGS (2005) J Clin Endocrinol Metab., 90, pp. 1966-1971Ranke, M.B., Lindberg, A., Chatelain, P., Prediction of long-term response to recombinant human growth hormone in Turner syndrome: Development and validation of mathematical models. KIGS International Board. Kabi International Growth Study (2000) J Clin Endocrinol Metab., 85, pp. 4212-4218Ranke, M.B., Lindberg, A., Cowell, C.T., Prediction of response to growth hormone treatment in short children born small for gestational age: Analysis of data from KIGS (Pharmacia International Growth Database) (2003) J Clin Endocrinol Metab., 88, pp. 125-131Clayton, P., Chatelain, P., Tato, L., Apharmacogenomic approach to the treatment of children withGHdeficiency or Turner syndrome (2013) Eur J Endocrinol., 169, pp. 277-289Stevens, A., Clayton, P., Tato, L., Pharmacogenomics of insulinlike growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome (2014) Pharmacogenomics J., 14, pp. 54-6

STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability

Diabetes mellitus: pathophysiological changes and therap

The Sitting Height/height Ratio For Age In Healthy And Short Individuals And Its Potential Role In Selecting Short Children For Shox Analysis

Aims: To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. Methods: Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). Results: The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10-22%), which was higher than in controls (1.4%, 95% CI 0.8-1.9%, p 2 were less common in children (48%, 95% CI 37-59%) and in adults (28%, 95% CI 20-36%) with TS. Conclusion: Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies. © 2013 S. Karger AG, Basel.806449456Ellison, J.W., Wardak, Z., Young, M.F., Gehron Robey, P., Laig-Webster, M., Chiong, W., PHOG, a candidate gene for involvement in the short stature of turner syndrome (1997) Hum Mol Genet, 6, pp. 1341-1347Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B., Mertz, A., Muroya, K., Rappold, G.A., Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome (1997) Nat Genet, 16, pp. 54-63Clement-Jones, M., Schiller, S., Rao, E., Blaschke, R.J., Zuniga, A., Zeller, R., Robson, S.C., Rappold, G.A., The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome (2000) Hum Mol Genet, 9, pp. 695-702Ross, J.L., Kowal, K., Quigley, C.A., Blum, W.F., Cutler Jr., G.B., Crowe, B., Hovanes, K., Zinn, A.R., The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: Contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome (2005) J Pediatr, 147, pp. 499-507Neufeld, N.D., Lippe, B.M., Kaplan, S.A., Disproportionate growth of the lower extremities. A major determinant of short stature in Turner's syndrome (1978) Am J Dis Child, 132, pp. 296-298Rongen-Westerlaken, C., Rikken, B., Vastrick, P., Jeuken, A.H., De Lange, M.Y., Wit, J.M., Van Der Tweel, L., Van Den Brande, J.L., Body proportions in individuals with Turner syndrome The Dutch growth hormone working group (1993) Eur J Pediatr, 152, pp. 813-817Gravholt, C.H., Weis Naeraa, R., Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome (1997) Am J Med Genet, 72, pp. 403-408Baldin, A.D., Armani, M.C., Morcillo, A.M., Lemos-Marini, S.H., Baptista, M.T., Maciel-Guerra, A.T., Guerra-Junior, G., Body proportions in a group of Brazilian patients with Turner syndrome (2005) Arq Bras Endocrinol Metabol, 49, pp. 529-535Jorge, A.A., Funari, M.F., Nishi, M.Y., Mendonca, B.B., Short stature caused by isolated SHOX gene haploinsufficiency: Update on the diagnosis and treatment (2010) Pediatr Endocrinol Rev, 8, pp. 79-85Ross, J.L., Scott Jr., C., Marttila, P., Kowal, K., Nass, A., Papenhausen, P., Abboudi, J., Zinn, A.R., Phenotypes associated with SHOX deficiency (2001) J Clin Endocrinol Metab, 86, pp. 5674-5680Binder, G., Ranke, M.B., Martin, D.D., Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in schoolage children with unexplained short stature (2003) J Clin Endocrinol Metab, 88, pp. 4891-4896Rappold, G., Blum, W.F., Shavrikova, E.P., Crowe, B.J., Roeth, R., Quigley, C.A., Ross, J.L., Niesler, B., Genotypes and phenotypes in children with short stature: Clinical indicators of SHOX haploinsufficiency (2007) J Med Genet, 44, pp. 306-313Jorge, A.A., Souza, S.C., Nishi, M.Y., Billerbeck, A.E., Liborio, D.C., Kim, C.A., Arnhold, I.J., Mendonca, B.B., SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: Frequency and phenotypic variability (2007) Clin Endocrinol (Oxf), 66, pp. 130-135Hirschfeldova, K., Solc, R., Baxova, A., Zapletalova, J., Kebrdlova, V., Gaillyova, R., Prasilova, S., Stekrova, J., SHOX gene defects and selected dysmorphic signs in patients of idiopathic short stature and Leri-Weill dyschondrosteosis (2012) Gene, 491, pp. 123-127Kant, S.G., Broekman, S.J., De Wit, C.C., Bos, M., Scheltinga, S.A., Bakker, E., Oostdijk, W., Losekoot, M., Phenotypic characterization of patients with deletions in the 3 ′ flanking SHOX region (2013) PeerJ, 1, pp. e35Fredriks, A.M., Van Buuren, S., Van Heel, W.J., Dijkman-Neerincx, R.H., Verloove-Vanhorick, S.P., Wit, J.M., Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders (2005) Arch Dis Child, 90, pp. 807-812Kuczmarski, R.J., Ogden, C.L., Grummer-Strawn, L.M., Flegal, K.M., Guo, S.S., Wei, R., Mei, Z., Johnson, C.L., CDC growth charts: United States (2000) Adv Data, 314, pp. 1-27Silva, D.A., Pelegrini, A., Petroski, E.L., Gaya, A.C., Comparison between the growth of Brazilian children and adolescents and the reference growth charts: Data from a Brazilian project (2010) J Pediatr (Rio J), 86, pp. 115-120Funari, M.F., Jorge, A.A., Souza, S.C., Billerbeck, A.E., Arnhold, I.J., Mendonca, B.B., Nishi, M.Y., Usefulness of MLPA in the detection of SHOX deletions (2010) Eur J Med Genet, 53, pp. 234-238Lango Allen, H., Estrada, K., Lettre, G., Berndt, S.I., Weedon, M.N., Rivadeneira, F., Willer, C.J., Hirschhorn, J.N., Hundreds of variants clustered in genomic loci and biological pathways affect human height (2010) Nature, 467, pp. 832-838Shears, D.J., Vassal, H.J., Goodman, F.R., Palmer, R.W., Reardon, W., Superti-Furga, A., Scambler, P.J., Winter, R.M., Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis (1998) Nat Genet, 19, pp. 70-73Belin, V., Cusin, V., Viot, G., Girlich, D., Toutain, A., Moncla, A., Vekemans, M., Cormier-Daire, V., SHOX mutations in dyschondrosteosis (Leri-Weill syndrome) (1998) Nat Genet, 19, pp. 67-69Rappold, G.A., Fukami, M., Niesler, B., Schiller, S., Zumkeller, W., Bettendorf, M., Heinrich, U., Ogata, T., Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature (2002) J Clin Endocrinol Metab, 87, pp. 1402-1406Jorge, A.A., Arnhold, I.J., Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature (2007) J Med Genet, 44, pp. e90. , author reply e91Kosho, T., Muroya, K., Nagai, T., Fujimoto, M., Yokoya, S., Sakamoto, H., Hirano, T., Ogata, T., Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: Implications for the development of turner syndrome (1999) J Clin Endocrinol Metab, 84, pp. 4613-4621Fukami, M., Nishi, Y., Hasegawa, Y., Miyoshi, Y., Okabe, T., Haga, N., Nagai, T., Ogata, T., Statural growth in 31 Japanese patients with SHOX haploinsufficiency: Support for a disadvantageous effect of gonadal estrogens (2004) Endocr J, 51, pp. 197-200Blum, W.F., Cao, D., Hesse, V., Fricke-Otto, S., Ross, J.L., Jones, C., Quigley, C.A., Binder, G., Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome (2009) Horm Res, 71, pp. 167-172Scalco, R.C., Melo, S.S., Pugliese-Pires, P.N., Funari, M.F., Nishi, M.Y., Arnhold, I.J., Mendonca, B.B., Jorge, A.A., Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency (2010) J Clin Endocrinol Metab, 95, pp. 328-33

Heterozygous STAT5b Gene Mutations: Impact on Clinical Phenotype

Developmen

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK ‐MODY and HNF1A ‐MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK ‐MODY and 55% with suspicion of HNF1A ‐MODY. Twenty‐five different variants were identified in GCK gene (30 probands—61% of positivity), and 7 variants in HNF1A (10 probands—17% of positivity). Fourteen of them were novel (12— GCK /2— HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%— GCK /86%— HNF1A ) and likely pathogenic (44%— GCK /14%— HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.924388396CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP304678/2012‐0Sem informação2013/19920‐

Supplementary Material for: GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects

<b><i>Background:</i></b> Mutations in GH-releasing hormone receptor gene <i>(GHRHR)</i> are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). <b><i>Objective:</i></b> To search for <i>GHRHR</i> mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. <b><i>Methods:</i></b> The coding region of <i>GHRHR</i> was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking <i>GHRHR</i> were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation. <b><i>Results:</i></b> A novel homozygous intronic <i>GHRHR</i> c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. <b><i>Conclusion:</i></b> We report a novel splice-disrupting mutation in <i>GHRHR</i> in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD

Supplementary Material for: Two Patients with Severe Short Stature due to a FBN1 Mutation (p.Ala1728Val) with a Mild Form of Acromicric Dysplasia

<p><b><i>Background:</i></b> Acromicric dysplasia (AD) and geleophysic dysplasia 2 (GD2) belong to the category of acromelic dysplasia syndromes, consisting of severe short stature, short hands and feet and skin thickening. Both can result from missense mutations in the transforming growth factor beta 5 domain of the fibrillin-1 gene <i>(FBN1)</i>. <b><i>Methods:</i></b> Two patients (P1 age 10, and P2 age 7) from unrelated families presented to their endocrinologist with severe short stature (approx. -4 SDS). They were otherwise asymptomatic and only had mild facial dysmorphisms. Extensive endocrine work-up did not reveal an underlying etiology. Exome sequencing was performed in each family. <b><i>Results:</i></b> Exome sequencing identified the presence of the same heterozygous missense variant c.C5183T (p.Ala1728Val) in the <i>FBN1</i> gene in both P1 and P2. This variant was previously reported in a patient with GD2 and associated cardiac valvulopathy and hepatomegaly. Detailed clinical re-examination, cardiac and skeletal imaging did not reveal any abnormalities in P1 or P2 other than mild hip dysplasia. <b><i>Conclusion:</i></b> This report broadens the phenotypic spectrum of growth disorders associated with <i>FBN1</i> mutations. Identical mutations give rise to a wide phenotypic spectrum, ranging from isolated short stature to a more classic picture of GD2 with cardiac involvement, distinct facial dysmorphisms and various skeletal anomalies.</p

Supplementary Material for: Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

<b><i>Background/Aims:</i></b> Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. <b><i>Methods:</i></b> We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. <b><i>Results:</i></b> We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. <b><i>Conclusion:</i></b> CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause