1 - Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisboa, Portugal;
2 - Instituto de Genética Médica y Molecular (INGEMM) e Skeletal dysplasia Multidisciplinary Unit, IdiPAZ, Hospital Universitario La Paz, UAM, Madrid, Espanha e CIBERER, ISCIII, Madrid, Espanha;
3 - Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal;
4 - Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal;
5 - Serviço de Genética Médica, Centro Hospitalar de São João, Porto, Portugal
6 - Unidade de Genética Médica, Hospital Dona Estefânia, Cento Hospitalar Lisboa Central, Lisboa, Portugal;
7 - Unidade de Genética Médica, Hospital de Braga, Braga, Portugal;
8 - Serviço de Pediatria, Hospital Dr. Nélio Mendonça, Funchal, Portugal;
9 - Serviço de Pediatria e Centro de Referência para Doenças Metabólicas, Centro Hospitalar Universitário do Porto, Porto, Portugal;
10 - Serviço de Ortopedia Infantil, Hospital Dona Estefânia, Cento Hospitalar Universitário Lisboa Central, Lisboa, Portugal;
11 - Serviço de Reumatologia, Hospital Garcia de Orta, Almada, Portugal;
12 - Serviço de Ortopedia Infantil, Hospital CUF, Lisboa, Portugal;
- Reunião da SPGH, Porto, 15 a 17 novembro de 2018
Resumo:
Introduction: Osteogenesis imperfecta (OI; prevalence 1/10-20.000) is a group of rare hereditary disorders characterized by increased susceptibility to bone fractures. OI is caused by type I collagen variants in 90% of cases while variants in a growing number of other genes have been identified in the remaining cases. Our aim was to characterize the clinical and mutational spectrum of OI in Portugal and to correlate genotype and phenotype.
Methods: Clinical data of OI patients were collected through analysis of patient medical records and clinical evaluation when indicated. Sanger and/or different next-generation sequencing (NGS) based strategies were used for molecular analysis. Only patients with a definitive clinical/molecular diagnosis of OI were considered.
Results: In total, 150 patients (47 children, 97 adults and 6 fetuses) of 121 families were included. Ninety-three cases were classified as mild OI, 29 as moderate, 19 as severe, and 7 as extremely severe (2 unclassifiable). The male to female ratio was 1:1,3. In 110 families (90.1%) and 92.7% (139/149) of total patients, 95 distinct pathogenic or likely pathogenic variants were identified in 7 different known OI genes: 65 in COL1A1, 19 in COL1A2, two each in SERPINF2, TMEM38B and BPM1 and one each in CRTAP, FKBP10, IFITM5, PPIB and WNT1; 42 are novel. Of the 123 type 1 collagen-related patients of 94 families, 78 had quantitative mutations and 45 had qualitative mutations. Autosomal recessive (AR) OI was diagnosed in 11 patients and heterozygous variants in severe AR OI genes were found in 4 patients with mild OI. After extended NGS analysis, a variant in a candidate gene was found in one, and no mutation was identified in six index cases.
Conclusions: This is the first study on OI in a large Portuguese cohort. Our results are in accordance with other populations: predominance of COL1A1/2 variants with higher frequency of quantitative mutations in patients with mild OI. Patients with IFITM5 and FKBP10-related OI had recognizable phenotypes. Molecular diagnosis in OI, besides genetic counselling, is progressively important for prognosis, presymptomatic testing and therapeutic recommendations.
Palavras Chave: Bone fragility, Collagen type I, Fractures, Genotype, Next-generation sequencing, Osteogenesis imperfecta, Phenotype, Sanger sequencing.