Phenotypic interpretation of complex chromosomal rearrangements informed by nucleotide-level resolution and structural organization of chromatin.
Eur J Hum Genet
; 26(3): 374-381, 2018 03.
Article
en En
| MEDLINE
| ID: mdl-29321672
ABSTRACT
Molecular characterization of balanced chromosomal abnormalities constitutes a powerful tool in understanding the pathogenic mechanisms of complex genetic disorders. Here we report a male with severe global developmental delay in the presence of a complex karyotype and normal microarray and exome studies. The subject, referred to as DGAP294, has two de novo apparently balanced translocations involving chromosomes 1 and 14, and chromosomes 4 and 10, disrupting several different transcripts of adhesion G protein-coupled receptor L2 (ADGRL2) and protocadherin 15 (PCDH15). In addition, a maternally inherited inversion disrupts peptidyl arginine deiminase types 3 and 4 (PADI3 and PADI4) on chromosome 1. None of these gene disruptions explain the patient's phenotype. Using genome regulatory annotations and chromosome conformation data, we predict a position effect ~370 kb upstream of a translocation breakpoint located at 14q12. The position effect involves forkhead box G1 (FOXG1), mutations in which are associated with the congenital form of Rett syndrome and FOXG1 syndrome. We believe the FOXG1 position effect largely accounts for the clinical phenotype in DGAP294, which can be classified as FOXG1 syndrome like. Our findings emphasize the significance of not only analyzing disrupted genes by chromosomal rearrangements, but also evaluating potential long-range position effects in clinical diagnoses.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
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Cromatina
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Discapacidades del Desarrollo
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Aberraciones Cromosómicas
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Trastornos de los Cromosomas
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Efectos de la Posición Cromosómica
Tipo de estudio:
Prognostic_studies
Límite:
Child
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Humans
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Male
Idioma:
En
Año:
2018
Tipo del documento:
Article