Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing - 21/11/19

Doi : 10.1016/j.jpeds.2019.08.024

Thais Kataoka Homma, MD ^1,^2,^{^{∗
Contributed equally.}}, Bruna Lucheze Freire, MSc ^1,^2,^{^{∗
Contributed equally.}}, Rachel Sayuri Honjo Kawahira, MD ³, Andrew Dauber, MD ⁴, Mariana Ferreira de Assis Funari, MSc ², Antônio Marcondes Lerario, MD ⁵, Mirian Yumie Nishi, MSc, PhD ², Edoarda Vasco de Albuquerque, MD ¹, Gabriela de Andrade Vasques, MD ¹, Paulo Ferrez Collett-Solberg, MD ⁶, Sofia Mizuho Miura Sugayama, MD ³, Debora Romeo Bertola, MD ³, Chong Ae Kim, MD ³, Ivo Jorge Prado Arnhold, MD ², Alexsandra Christianne Malaquias, MD ^1,⁷, Alexander Augusto de Lima Jorge, MD ^1,^2,^⁎
¹ Genetic Endocrinology Unit, Laboratory of Cellular and Molecular Endocrinology (LIM25), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil
² Development Endocrinology Unit, Laboratory of Hormones and Molecular Genetics (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Brazil
³ Genetic Unit of the Instituto da Criança, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Brazil
⁴ Division of Endocrinology, Children's National Health System, USA
⁵ Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, USA
⁶ Endocrinology Discipline of the Faculdade de Ciência Médicas da Universidade do Estado do Rio de Janeiro - FCM/UERJ, Rio de Janeiro, Brazil
⁷ Pediatric Endocrinology Unit, Department of Pediatrics, Irmandade da Santa Casa de Misericórdia de São Paulo, Faculdade de Ciências Médicas da Santa Casa de São Paulo, Brazil

^∗Reprint requests: Alexander Augusto de Lima Jorge, MD, PhD, Genetic Endocrinology Unit, University of Sao Paulo, Avenida Dr. Arnaldo, 455, 5º andar, sala 5, 01246-903 Sao Paulo, Brazil.Genetic Endocrinology UnitUniversity of Sao PauloAvenida Dr. Arnaldo455, 5º andarsala 5Sao Paulo01246-903Brazil

Abstract

Objective

To perform a prospective genetic investigation using whole exome sequencing of a group of patients with syndromic short stature born small for gestational age of unknown cause.

Study design

For whole exome sequencing analysis, we selected 44 children born small for gestational age with persistent short stature, and additional features, such as dysmorphic face, major malformation, developmental delay, and/or intellectual disability. Seven patients had negative candidate gene testing based on clinical suspicion and 37 patients had syndromic conditions of unknown etiology.

Results

Of the 44 patients, 15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each). Most of the genes found to be deleterious participate in fundamental cellular processes, such as cell replication and DNA repair.

Conclusions

The rarity and heterogeneity of syndromic short stature make the clinical diagnosis difficult. Whole exome sequencing allows the diagnosis of previously undiagnosed patients with syndromic short stature.

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Keywords : growth disorder, short stature, small for gestational age, intrauterine growth retardation, syndrome, whole exome sequencing

Abbreviations : CAPPesq, SGA, USP, WES

Plan

Supported by grants 2013/03236–5 (to A.J.), 2015/26980-7 (to T.H.), and SELA – the Laboratório de Sequenciamento em Larga Escala from the São Paulo Research Foundation (FAPESP) (2014/50137-5); and the National Council for Scientific and Technological Development (CNPq) (304678/2012–0 [to A.J.]). The authors declare no conflicts of interest.

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Vol 215

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Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing - 21/11/19

Abstract

Objective

Study design

Results

Conclusions

Plan

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