RESUMEN
Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel-like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel-like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anomalías , Síndrome de Dandy-Walker/genética , Predisposición Genética a la Enfermedad , Malformaciones del Sistema Nervioso/genética , Quiste Pancreático/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/patología , Adolescente , Adulto , Cerebelo/patología , Niño , Preescolar , Síndrome de Dandy-Walker/epidemiología , Síndrome de Dandy-Walker/patología , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Femenino , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Microcefalia/epidemiología , Microcefalia/genética , Microcefalia/patología , Mutación , Mutación Missense , Malformaciones del Sistema Nervioso/epidemiología , Malformaciones del Sistema Nervioso/patología , Quiste Pancreático/epidemiología , Quiste Pancreático/patología , Linaje , Fenotipo , Embarazo , Adulto JovenRESUMEN
To assess the clinical utility of genome-wide oligonucleotide arrays in diagnosis of mental retardation and to address issues relating to interpretation of copy number changes (CNCs), we collected results on a total of 1499 proband patients from five academic diagnostic laboratories where the same 44K array platform has been used. Three of the five laboratories achieved a diagnostic yield of 14% and the other two had a yield of 11 and 7%, respectively. Approximately 80% of the abnormal cases had a single segment deletion or duplication, whereas the remaining 20% had a compound genomic imbalance involving two or more DNA segments. Deletion of 16p11.2 is a common microdeletion syndrome associated with mental retardation. We classified pathogenic CNCs into six groups according to the structural changes. Our data have demonstrated that the 44K platform provides a reasonable resolution for clinical use and a size of 300 kb can be used as a practical cutoff for further investigations of the clinical relevance of a CNC detected with this platform. We have discussed in depth the issues associated with the clinical use of array CGH and provided guidance for interpretation, reporting, and counseling of test results based on our experience.