Sistema de Salut de Catalunya
Institut Català de la Salut
[Nevado J, García-Miñaúr S, Palomares-Bralo M, Vallespín E] Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain. CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain. ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain. [Guillén-Navarro E] Hospital Virgen de la Arrixaca, Murcia, Spain. [Rosell J] Hospital Son Espases, Palma de Mallorca, Spain. [del Campo M] Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2023-01-12T13:07:42Z
2023-01-12T13:07:42Z
2022-04-12
Phelan-McDermid syndrome; Intellectual disabilities; Subtelomeric deletion syndrome
Síndrome de Phelan-McDermid; Discapacidades intelectuales; Síndrome de deleción subtelomérica
Síndrome de Phelan-McDermid; Discapacitats intel·lectuals; Síndrome de deleció subtelomèrica
Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.
REDES/FIBHULP08. FIBHULP PI: 2735. FIBHULP Auchan Reserch Project. FIBHULP. Raregenomics (B2017/BMD-3721).
Article
Published version
English
Cromosomes humans - Anomalies; Malalties congènites; Polimorfisme genètic; Other subheadings::Other subheadings::Other subheadings::/genetics; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Genomic Structural Variation::DNA Copy Number Variations; PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders; DISEASES::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Chromosome Disorders; ENFERMEDADES::enfermedades y anomalías neonatales congénitas y hereditarias::anomalías congénitas::trastornos cromosómicos; Otros calificadores::Otros calificadores::Otros calificadores::/genética; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::polimorfismo genético::variación estructural genómica::variaciones del número de copias de ADN; PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico
Frontiers Media
Frontiers in Genetics;13
https://doi.org/10.3389/fgene.2022.652454
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - HVH [3440]
