title: Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing.
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 (∼1.5-5 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.
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors: Andrew
authors: A
authors: Kirby
authors: Andreas
authors: A
authors: Gnirke
authors: David B
authors: DB
authors: Jaffe
authors: Veronika
authors: V
authors: Barešová
authors: Nathalie
authors: N
authors: Pochet
authors: Brendan
authors: B
authors: Blumenstiel
authors: Chun
authors: C
authors: Ye
authors: Daniel
authors: D
authors: Aird
authors: Christine
authors: C
authors: Stevens
authors: James T
authors: JT
authors: Robinson
authors: Moran N
authors: MN
authors: Cabili
authors: Irit
authors: I
authors: Gat-Viks
authors: Edward
authors: E
authors: Kelliher
authors: Riza
authors: R
authors: Daza
authors: Matthew
authors: M
authors: DeFelice
authors: Helena
authors: H
authors: Hůlková
authors: Jana
authors: J
authors: Sovová
authors: Petr
authors: P
authors: Vylet'al
authors: Corinne
authors: C
authors: Antignac
authors: Mitchell
authors: M
authors: Guttman
authors: Robert E
authors: RE
authors: Handsaker
authors: Danielle
authors: D
authors: Perrin
authors: Scott
authors: S
authors: Steelman
authors: Snaevar
authors: S
authors: Sigurdsson
authors: Steven J
authors: SJ
authors: Scheinman
authors: Carrie
authors: C
authors: Sougnez
authors: Kristian
authors: K
authors: Cibulskis
authors: Melissa
authors: M
authors: Parkin
authors: Todd
authors: T
authors: Green
authors: Elizabeth
authors: E
authors: Rossin
authors: Michael C
authors: MC
authors: Zody
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Martin R
authors: MR
authors: Pollak
authors: Seth L
authors: SL
authors: Alper
authors: Kerstin
authors: K
authors: Lindblad-Toh
authors: Stacey
authors: S
authors: Gabriel
authors: P Suzanne
authors: PS
authors: Hart
authors: Aviv
authors: A
authors: Regev
authors: Chad
authors: C
authors: Nusbaum
authors: Stanislav
authors: S
authors: Kmoch
authors: Anthony J
authors: AJ
authors: Bleyer
authors: Eric S
authors: ES
authors: Lander
authors: Mark J
authors: MJ
authors: Daly
mesh_terms: D003596:Cytosine / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000473:pathology
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D003596:Cytosine
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