Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals
Por:
Nevado J, García-Miñaúr S, Palomares-Bralo M, Vallespín E, Guillén-Navarro E, Rosell J, Bel-Fenellós C, Mori MÁ, Milá M, Del Campo M, Barrúz P, Santos-Simarro F, Obregón G, Orellana C, Pachajoa H, Tenorio JA, Galán E, Cigudosa JC, Moresco A, Saleme C, Castillo S, Gabau E, Pérez-Jurado L, Barcia A, Martín MS, Mansilla E, Vallcorba I, García-Murillo P, Cammarata-Scalisi F, Gonçalves Pereira N, Blanco-Lago R, Serrano M, Ortigoza-Escobar JD, Gener B, Seidel VA, Tirado P and Lapunzina P
Publicada:
12 abr 2022
Ahead of Print:
12 abr 2022
Resumen:
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.
Filiaciones:
Nevado J:
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
García-Miñaúr S:
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
Palomares-Bralo M:
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
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
Bel-Fenellós C:
Departamento de Investigación y Psicología en Educación, Facultad de Educación, UCM, Madrid, Spain
CEE Estudio-3, Afanias, Madrid, Spain
Mori MÁ:
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
Milá M:
Hospital Clinic, Barcelona, Spain
Del Campo M:
Hospital Vall d'Hebrón, Barcelona, Spain
Barrúz P:
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
Santos-Simarro F:
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
Obregón G:
Hospìtal Juan P. Garrahan, Buenos Aires, Argentina
Orellana C:
Hospital La Fe, Valencia, Spain
Pachajoa H:
Universidad Icesi, Cali, Colombia
Tenorio JA:
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
Galán E:
Hospital Materno-Infantil Infanta Cristina, Badajoz, Spain
Cigudosa JC:
NIM-Genetics Madrid, Alcobendas, Spain
Moresco A:
Hospìtal Juan P. Garrahan, Buenos Aires, Argentina
Saleme C:
Maternity Nuestra Señora de la Merced, Tucumán, Argentina
Castillo S:
Sección Genética, Hospital Clínico Universidad de Chile, Santiago, Chile
Clínica Alemana, Santiago, Chile
Gabau E:
Corporación Sanitaria Parc Taulí, Barcelona, Spain
Pérez-Jurado L:
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
Servicio de Genética, Instituto de Investigaciones Médicas Hospital del Mar (IMIM)/Universitat Pompeu Fabra, Barcelona, Spain
Barcia A:
Hospital Universitario Virgen del Rocío, Sevilla, Spain
Martín MS:
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
Mansilla 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
Vallcorba I:
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
García-Murillo P:
Unidad de Genética, Hospital Virgen de la Salud, Toledo, Spain
Cammarata-Scalisi F:
Servicio de Pediatría, Hospital Regional de Antofagasta, Antofagasta, Chile
Gonçalves Pereira N:
Clínica Reprodutiva NIDUS, Juiz de Fora, Brasil
Blanco-Lago R:
Servicio de Neuropediatría, Hospital Universitario Central de Asturias, Oviedo (Asturias), Spain
Serrano M:
Unidad de Neuropediatría, Hospital San Joan de Deu, Barcelona, Spain
Ortigoza-Escobar JD:
Unidad de Neuropediatría, Hospital San Joan de Deu, Barcelona, Spain
Gener B:
Hospital Universitario de Cruces, Bilbao, Spain
Seidel VA:
Servicio de Genética Clínica, Hospital Universitario Gregorio Marañon, Madrid, Spain
Tirado P:
Servicio de Neuropediatría, Hospital Universitario La Paz, Madrid, Spain
Lapunzina P:
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
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