Ana P M Canton, Sílvia S Costa, Tatiane C Rodrigues, Debora R Bertola, Alexsandra C Malaquias, Fernanda A Correa, Ivo J P Arnhold, Carla Rosenberg and Alexander A L Jorge
The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.
To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.
Patients and methods
A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.
In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.
Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.
Edoarda Vasco de Albuquerque Albuquerque, Mariana Ferreira de Assis Funari, Elisângela Pereira de Souza Quedas, Rachel Sayuri Honjo Kawahira, Raquel Soares Jallad, Thaís Kataoka Homma, Regina Matsunaga Martin, Vinicius Nahime Brito, Alexsandra Christianne Malaquias, Antonio Marcondes Lerario, Carla Rosenberg, Ana Cristina Victorino Krepischi, Chong Ae Kim, Ivo Jorge Prado Arnhold and Alexander Augusto de Lima Jorge
Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach.
To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder.
Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31).
Patients and methods
We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups.
Main outcome measures
Frequencies of pathogenic findings.
We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith–Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients.
A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.