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A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case
BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 ha...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637483/ https://www.ncbi.nlm.nih.gov/pubmed/31319798 http://dx.doi.org/10.1186/s11689-019-9273-1 |
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author | Samogy-Costa, Claudia Ismania Varella-Branco, Elisa Monfardini, Frederico Ferraz, Helen Fock, Rodrigo Ambrósio Barbosa, Ricardo Henrique Almeida Pessoa, André Luiz Santos Perez, Ana Beatriz Alvarez Lourenço, Naila Vibranovski, Maria Krepischi, Ana Rosenberg, Carla Passos-Bueno, Maria Rita |
author_facet | Samogy-Costa, Claudia Ismania Varella-Branco, Elisa Monfardini, Frederico Ferraz, Helen Fock, Rodrigo Ambrósio Barbosa, Ricardo Henrique Almeida Pessoa, André Luiz Santos Perez, Ana Beatriz Alvarez Lourenço, Naila Vibranovski, Maria Krepischi, Ana Rosenberg, Carla Passos-Bueno, Maria Rita |
author_sort | Samogy-Costa, Claudia Ismania |
collection | PubMed |
description | BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. METHODOLOGY: A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. RESULTS: Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. CONCLUSIONS: This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s11689-019-9273-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6637483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66374832019-07-25 A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case Samogy-Costa, Claudia Ismania Varella-Branco, Elisa Monfardini, Frederico Ferraz, Helen Fock, Rodrigo Ambrósio Barbosa, Ricardo Henrique Almeida Pessoa, André Luiz Santos Perez, Ana Beatriz Alvarez Lourenço, Naila Vibranovski, Maria Krepischi, Ana Rosenberg, Carla Passos-Bueno, Maria Rita J Neurodev Disord Research BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. METHODOLOGY: A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. RESULTS: Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. CONCLUSIONS: This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s11689-019-9273-1) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-18 /pmc/articles/PMC6637483/ /pubmed/31319798 http://dx.doi.org/10.1186/s11689-019-9273-1 Text en © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Samogy-Costa, Claudia Ismania Varella-Branco, Elisa Monfardini, Frederico Ferraz, Helen Fock, Rodrigo Ambrósio Barbosa, Ricardo Henrique Almeida Pessoa, André Luiz Santos Perez, Ana Beatriz Alvarez Lourenço, Naila Vibranovski, Maria Krepischi, Ana Rosenberg, Carla Passos-Bueno, Maria Rita A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title | A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title_full | A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title_fullStr | A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title_full_unstemmed | A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title_short | A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case |
title_sort | brazilian cohort of individuals with phelan-mcdermid syndrome: genotype-phenotype correlation and identification of an atypical case |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637483/ https://www.ncbi.nlm.nih.gov/pubmed/31319798 http://dx.doi.org/10.1186/s11689-019-9273-1 |
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