High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

Abstract

Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.

Phenotypic spectrum of TGFB3 disease‐causing variants in a Dutch‐French cohort and first report of a homozygous patient

“…No more than 50 patients carrying disease‐causing TGFB3 variants have been reported so far . Here, we described genetic and clinical data from 32 TGFB3 patients from 17 families including the first homozygous individual.…”

“…Given the rarity of the disorder, with no more than 50 cases described so far, a precise delineation of its phenotype is yet to be determined …”

A novel stopgain mutation c.G992A (p.W331X) in TACR3 gene was identified in nonobstructive azoospermia by targeted next‐generation sequencing

“…Duplicated reads from library and PCR preparation were removed with Picard tools. After alignment to the human reference genome (GRCh37/hg19), most likely nondeleterious variants were filtered as previously described . Variants with minor allele frequencies greater than 1% in the databases including dbSNP, 1000 Genomes Project, Exome Aggregation Consortium, Exome Variant Server, were excluded because they were unlikely to be deleterious.…”

“…After alignment to the human reference genome (GRCh37/hg19), most likely nondeleterious variants were filtered as previously described. 19 Variants with minor allele frequencies greater than 1% in the databases including dbSNP, 1000 Genomes Project, Exome Aggregation Consortium, Exome Variant Server, were excluded because they were unlikely to be deleterious. Intronic variants and synonymous variants that were located within intronic regions, regulatory regions and nonregulatory intergenic regions were excluded.…”

Investigação genético-molecular da baixa estatura isolada através de sequenciamento paralelo em larga escala

“…É importante ressaltar que nesse trabalho, 51% dos pacientes já havia sido submetido a uma análise molecular prévia de pelo menos um dos três principais genes associados à baixa estatura isolada (SHOX, NPR2 e FGFR3). Esse fato pode ter diminuído a nossa taxa de positividade.Os estudos prévios que utilizaram metodologias de sequenciamento paralelo em larga escala para investigar a causa de pacientes com baixa estatura apresentam taxas de positividade muito diferentes, variando de 2 a 46%(101)(102)(103)(104)(105).Essa grande variação pode ser consequência das diferenças nas metodologias aplicadas e nos grupos de pacientes avaliados nesses trabalhos, tanto em relação ao número de indivíduos estudados como ao fenótipo que eles apresentavam. Um trabalho realizado recentemente pelo nosso grupo avaliou 55 pacientes com baixa estatura isolada nascidos pequenos para a idade gestacional, por SPLE, sendo 39 deles por um painel customizado com genes relacionados ao crescimento, e os demais por exoma(106).…”