A Brazilian cohort of individuals with Phelan-McDermid syndrome

genotype-phenotype correlation and identification of an atypical case

Claudia Ismania Samogy-Costa, Elisa Varella-Branco, Frederico Monfardini, Helen Ferraz, Rodrigo Ambrósio Fock, Ricardo Henrique Almeida Barbosa, André Luiz Santos Pessoa, Ana Beatriz Alvarez Perez, Naila Lourenço, Maria Vibranovski, Ana C.V. Krepischi, Carla Rosenberg, Maria Rita Passos-Bueno

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Number of pages1
JournalJournal of neurodevelopmental disorders
Volume11
Issue number1
DOIs
StatePublished - Jul 18 2019

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Genetic Association Studies
Intellectual Disability
Comorbidity
Muscle Hypotonia
Lymphedema
Telomeric 22q13 Monosomy Syndrome
Eyebrows
Kidney
Haploinsufficiency
Mutation
Inborn Genetic Diseases
Reference Values
Language
Autism Spectrum Disorder
Phenotype
Pain

Keywords

  • 22q13.3 deletion syndrome
  • Autism spectrum disorder
  • Phelan-McDermid syndrome
  • SHANK3

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Samogy-Costa, C. I., Varella-Branco, E., Monfardini, F., Ferraz, H., Fock, R. A., Barbosa, R. H. A., ... Passos-Bueno, M. R. (2019). A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case. Journal of neurodevelopmental disorders, 11(1). https://doi.org/10.1186/s11689-019-9273-1

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 C.V.; Rosenberg, Carla; Passos-Bueno, Maria Rita.

In: Journal of neurodevelopmental disorders, Vol. 11, No. 1, 18.07.2019.

Research output: Contribution to journalArticle

Samogy-Costa, CI, Varella-Branco, E, Monfardini, F, Ferraz, H, Fock, RA, Barbosa, RHA, Pessoa, ALS, Perez, ABA, Lourenço, N, Vibranovski, M, Krepischi, ACV, Rosenberg, C & Passos-Bueno, MR 2019, 'A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case', Journal of neurodevelopmental disorders, vol. 11, no. 1. https://doi.org/10.1186/s11689-019-9273-1
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 C.V. ; Rosenberg, Carla ; Passos-Bueno, Maria Rita. / A Brazilian cohort of individuals with Phelan-McDermid syndrome : genotype-phenotype correlation and identification of an atypical case. In: Journal of neurodevelopmental disorders. 2019 ; Vol. 11, No. 1.
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abstract = "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.",
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T1 - A Brazilian cohort of individuals with Phelan-McDermid syndrome

T2 - genotype-phenotype correlation and identification of an atypical case

AU - Samogy-Costa, Claudia Ismania

AU - Varella-Branco, Elisa

AU - Monfardini, Frederico

AU - Ferraz, Helen

AU - Fock, Rodrigo Ambrósio

AU - Barbosa, Ricardo Henrique Almeida

AU - Pessoa, André Luiz Santos

AU - Perez, Ana Beatriz Alvarez

AU - Lourenço, Naila

AU - Vibranovski, Maria

AU - Krepischi, Ana C.V.

AU - Rosenberg, Carla

AU - Passos-Bueno, Maria Rita

PY - 2019/7/18

Y1 - 2019/7/18

N2 - 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.

AB - 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.

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KW - Autism spectrum disorder

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KW - SHANK3

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