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Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome

SALL1 heterozygous pathogenic variants cause Townes–Brocks syndrome (TBS), a condition with variable clinical presentation. The main features are a stenotic or imperforate anus, dysplastic ears, and thumb malformations, and other common concerns are hearing impairments, foot malformations, and renal...

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Autores principales: Innoceta, Anna Maria, Olivucci, Giulia, Parmeggiani, Giulia, Scarano, Emanuela, Pragliola, Antonella, Graziano, Claudio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956891/
https://www.ncbi.nlm.nih.gov/pubmed/36833185
http://dx.doi.org/10.3390/genes14020258
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author Innoceta, Anna Maria
Olivucci, Giulia
Parmeggiani, Giulia
Scarano, Emanuela
Pragliola, Antonella
Graziano, Claudio
author_facet Innoceta, Anna Maria
Olivucci, Giulia
Parmeggiani, Giulia
Scarano, Emanuela
Pragliola, Antonella
Graziano, Claudio
author_sort Innoceta, Anna Maria
collection PubMed
description SALL1 heterozygous pathogenic variants cause Townes–Brocks syndrome (TBS), a condition with variable clinical presentation. The main features are a stenotic or imperforate anus, dysplastic ears, and thumb malformations, and other common concerns are hearing impairments, foot malformations, and renal and heart defects. Most of the pathogenic SALL1 variants are nonsense and frameshift, likely escaping nonsense-mediated mRNA decay and causing disease via a dominant-negative mechanism. Haploinsufficiency may result in mild phenotypes, but only four families with distinct SALL1 deletions have been reported to date, with a few more being of larger size and also affecting neighboring genes. We report on a family with autosomal dominant hearing impairment and mild anal and skeletal anomalies, in whom a novel 350 kb SALL1 deletion, spanning exon 1 and the upstream region, was identified by array comparative genomic hybridization. We review the clinical findings of known individuals with SALL1 deletions and point out that the overall phenotype is milder, especially when compared with individuals who carry the recurrent p.Arg276Ter mutation, but with a possible higher risk of developmental delay. Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated.
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spelling pubmed-99568912023-02-25 Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome Innoceta, Anna Maria Olivucci, Giulia Parmeggiani, Giulia Scarano, Emanuela Pragliola, Antonella Graziano, Claudio Genes (Basel) Article SALL1 heterozygous pathogenic variants cause Townes–Brocks syndrome (TBS), a condition with variable clinical presentation. The main features are a stenotic or imperforate anus, dysplastic ears, and thumb malformations, and other common concerns are hearing impairments, foot malformations, and renal and heart defects. Most of the pathogenic SALL1 variants are nonsense and frameshift, likely escaping nonsense-mediated mRNA decay and causing disease via a dominant-negative mechanism. Haploinsufficiency may result in mild phenotypes, but only four families with distinct SALL1 deletions have been reported to date, with a few more being of larger size and also affecting neighboring genes. We report on a family with autosomal dominant hearing impairment and mild anal and skeletal anomalies, in whom a novel 350 kb SALL1 deletion, spanning exon 1 and the upstream region, was identified by array comparative genomic hybridization. We review the clinical findings of known individuals with SALL1 deletions and point out that the overall phenotype is milder, especially when compared with individuals who carry the recurrent p.Arg276Ter mutation, but with a possible higher risk of developmental delay. Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated. MDPI 2023-01-19 /pmc/articles/PMC9956891/ /pubmed/36833185 http://dx.doi.org/10.3390/genes14020258 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Innoceta, Anna Maria
Olivucci, Giulia
Parmeggiani, Giulia
Scarano, Emanuela
Pragliola, Antonella
Graziano, Claudio
Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title_full Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title_fullStr Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title_full_unstemmed Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title_short Chromosomal Microarray Analysis Identifies a Novel SALL1 Deletion, Supporting the Association of Haploinsufficiency with a Mild Phenotype of Townes–Brocks Syndrome
title_sort chromosomal microarray analysis identifies a novel sall1 deletion, supporting the association of haploinsufficiency with a mild phenotype of townes–brocks syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956891/
https://www.ncbi.nlm.nih.gov/pubmed/36833185
http://dx.doi.org/10.3390/genes14020258
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