Genotype-Phenotype Correlation in Brazilian Patients with Phelan-Mcdermid Syndrome : New Insights for a Better Clinical and Genetic Counseling Management
Phelan-McDermid Syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability and mild dysmorphisms associated with several comorbidities. PMS results from SHANK3 loss of function, mainly caused by copy number variations (CNVs) of different sizes. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the great clinical variability seen among patients.
Our goals were to characterize a Brazilian cohort of PMS patients, explore the genotype-phenotype correlation underlying this syndrome and estimate the frequency of PMS among ASD and ID individuals.
A total of 34 PMS patients were clinically and genetically evaluated. The data were obtained by a questionnaire answered by parents and dismorphic features were evaluated using patients’ pictures. We have analysed the 22q13.3 CNVs and and other potentially pathogenic CNVs. We also performed a genotype-phenotype correlation analysis in order to determine whether comorbidities, speech status and autism spectrum disorder correlate with deletion size. Finally, a cohort composed by 829 ASD individuals and another composed by 2297 ID patients were used to determine the frequency of PMS among these disorders.
In our clinical data, sparse eyebrows were a prominent clinical feature (80%). Genotype-phenotype correlation allowed us to restrict minimum regions of deletion at 22q13.3 which are neither associated with renal complications (<1.3 Mb) or with lymphedema (<4.3Mb). We also confirmed a positive association between language impairment and deletion size. About 21% of the patients showed an additional rare CNV, which may contribute to a more severe phenotype or clinical features not commonly seen in PMS. Among ASD Brazilian or ID patients referred to CNV analyses the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.65% (15/2297), respectively, confirming its relevance among neurodevelopmental disorders.
To date, this is the first work describing a cohort of Brazilian patients with PMS and it highlights the importance of second hits in this condition. Taken together, our data show that the clinical history of PMS in a different ethnicity and culture did not differ significantly from other countries, which represents a baseline for any future management.