A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype- phenotype correlation and identification of an atypical case
| Autor: | Ricardo Henrique Almeida Barbosa, Helen Conceição Ferraz, Ana Beatriz Alvarez Perez, Carla Rosenberg, Claudia Ismania Samogy-Costa, Rodrigo Ambrosio Fock, Maria Rita Passos-Bueno, André Pessoa, Frederico Monfardini, Elisa Varella-Branco, Maria D. Vibranovski, Ana Cristina Victorino Krepischi, Naila Cristina Vilaça Lourenço |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Pediatrics Chromosomes Human Pair 22 Chromosome Disorders Cohort Studies 0302 clinical medicine Intellectual disability Global developmental delay Copy-number variation Autism spectrum disorder Child SHANK3 05 social sciences Genetic disorder Hypotonia Child Preschool Cohort Female Chromosome Deletion medicine.symptom Haploinsufficiency Brazil 050104 developmental & child psychology Adult medicine.medical_specialty Adolescent DNA Copy Number Variations 22q13.3 deletion syndrome Cognitive Neuroscience Nerve Tissue Proteins lcsh:RC321-571 Pathology and Forensic Medicine Young Adult 03 medical and health sciences medicine Humans 0501 psychology and cognitive sciences lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Genetic Association Studies business.industry Research Infant DELEÇÃO DE GENES medicine.disease Pediatrics Perinatology and Child Health Phelan-McDermid syndrome Neurology (clinical) business 030217 neurology & neurosurgery |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Journal of Neurodevelopmental Disorders, Vol 11, Iss 1, Pp 1-10 (2019) Journal of Neurodevelopmental Disorders |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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