Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing.
Nat Genet
; 45(3): 299-303, 2013 Mar.
Article
in En
| MEDLINE
| ID: mdl-23396133
ABSTRACT
Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (â¼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
Full text:
1
Database:
MEDLINE
Main subject:
Polycystic Kidney, Autosomal Dominant
/
Minisatellite Repeats
/
Mucin-1
/
Mutation
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2013
Type:
Article
Affiliation country:
United States