RESUMEN
BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
Asunto(s)
Secuenciación del Exoma , Familia , Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Canadá/epidemiología , Preescolar , Consanguinidad , Femenino , Enfermedades Genéticas Congénitas/epidemiología , Pruebas Genéticas , Genotipo , Humanos , Masculino , Mutación , Linaje , Fenotipo , Estudios Retrospectivos , Hermanos , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Cardio-facio-cutaneous syndrome (CFC) is a multiple congenital anomaly/mental retardation syndrome named because of a characteristic facies, cardiac anomalies, and ectodermal abnormalities. While considerable literature describes the main features, few studies have documented the frequencies of less common features allowing a greater appreciation of the full phenotype. METHODS: We have analysed clinical data on 38 individuals with CFC and a confirmed mutation in one of the genes known to cause the condition. We provide data on well-established features, and those that are less often described. RESULTS: Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. 71% of individuals had a cardiac anomaly, the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: 92% had curly hair, 84% sparse hair, and 86% absent or sparse eyebrows. The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%) and nevi (76%). Significant and long lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%) and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported. CONCLUSION: This study reports a broad range of clinical issues in a large cohort of individuals with molecular confirmation of CFC.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Displasia Ectodérmica/genética , Cardiopatías Congénitas/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/genética , Masculino , Mutación , Fenotipo , Embarazo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Síndrome , Proteínas ras/genéticaAsunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 5/genética , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Cromosomas Humanos Par 17/genética , Femenino , Dedos/anomalías , Deformidades Congénitas del Pie/clasificación , Deformidades Congénitas de la Mano/clasificación , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Linaje , Polimorfismo Genético/genética , Programas InformáticosRESUMEN
The brachydactylies are a group of conditions in which various subtypes have been defined based upon the specific pattern of digital bones involved. Type A1 brachydactyly is principally characterised by maximal involvement of the middle phalanges. We report an extended family with a mild brachydactyly A1 which was, except for some short stature, not associated with any of the additional clinical findings reported in several published families. While all the hand bones tended to be small, the principal features of the affected members were shortened middle and distal phalanges, proximal 1st phalanges, and 5th metacarpals. The feet were similarly involved and tended to have a broad, slightly adducted forefoot. The two affected children showed multiple coned epiphyses. This paper provides a detailed description of the family including the radiographic signs and metacarpophalangeal profiles, which proved to be useful in distinguishing the mildly affected persons.