Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1.
Am J Med Genet A
; 182(7): 1631-1636, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-32412173
ABSTRACT
Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results:
258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas
/
Seudogenes
/
Secuenciación del Exoma
/
Síndrome de Shwachman-Diamond
Límite:
Female
/
Humans
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Infant
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Male
/
Newborn
Idioma:
En
Revista:
Am J Med Genet A
Asunto de la revista:
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Japón