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Am J Hum Genet. 2014 May 1;94(5):745-54. doi: 10.1016/j.ajhg.2014.03.017. Epub 2014 Apr 17.

Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.

Author information

1
Center for Human Disease Modeling, Duke University School of Medicine, Durham, NC 27710, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Division of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
5
Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92359, USA.
6
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
7
Center for Retinal and Macular Degenerations, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
9
Center for Human Disease Modeling, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: nicholas.katsanis@duke.edu.

Abstract

Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.

PMID:
24746959
PMCID:
PMC4067552
DOI:
10.1016/j.ajhg.2014.03.017
[Indexed for MEDLINE]
Free PMC Article

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