Haplotype-based analysis resolves missing heritability in oculocutaneous albinism type 1B.
albinism
foveal hypoplasia
haplotype
hypopigmentation
missing genetic heritability
oculocutaneous albinism
pigmentation
tyrosinase
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 07 2023
06 07 2023
Historique:
received:
26
12
2022
revised:
19
05
2023
accepted:
22
05
2023
pmc-release:
06
01
2024
medline:
10
7
2023
pubmed:
17
6
2023
entrez:
16
6
2023
Statut:
ppublish
Résumé
Oculocutaneous albinism (OCA) is a rare disorder of pigment production. Affected individuals have variably decreased global pigmentation and visual-developmental changes that lead to low vision. OCA is notable for significant missing heritability, particularly among individuals with residual pigmentation. Tyrosinase (TYR) is the rate-limiting enzyme in melanin pigment biosynthesis and mutations that decrease enzyme function are one of the most common causes of OCA. We present the analysis of high-depth short-read TYR sequencing data for a cohort of 352 OCA probands, ∼50% of whom were previously sequenced without yielding a definitive diagnostic result. Our analysis identified 66 TYR single-nucleotide variants (SNVs) and small insertion/deletions (indels), 3 structural variants, and a rare haplotype comprised of two common frequency variants (p.Ser192Tyr and p.Arg402Gln) in cis-orientation, present in 149/352 OCA probands. We further describe a detailed analysis of the disease-causing haplotype, p.[Ser192Tyr; Arg402Gln] ("cis-YQ"). Haplotype analysis suggests that the cis-YQ allele arose by recombination and that multiple cis-YQ haplotypes are segregating in OCA-affected individuals and control populations. The cis-YQ allele is the most common disease-causing allele in our cohort, representing 19.1% (57/298) of TYR pathogenic alleles in individuals with type 1 (TYR-associated) OCA. Finally, among the 66 TYR variants, we found several additional alleles defined by a cis-oriented combination of minor, potentially hypomorph-producing alleles at common variant sites plus a second, rare pathogenic variant. Together, these results suggest that identification of phased variants for the full TYR locus are required for an exhaustive assessment for potentially disease-causing alleles.
Identifiants
pubmed: 37327787
pii: S0002-9297(23)00169-6
doi: 10.1016/j.ajhg.2023.05.012
pmc: PMC10357474
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1123-1137Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
J Exp Med. 2000 Mar 20;191(6):1005-16
pubmed: 10727462
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Exp Eye Res. 2013 Jun;111:9-16
pubmed: 23523800
J Biol Chem. 1992 Nov 25;267(33):23707-12
pubmed: 1429711
Commun Biol. 2019 May 20;2:186
pubmed: 31123710
NPJ Genom Med. 2022 Jan 13;7(1):2
pubmed: 35027574
Nat Commun. 2022 Jul 8;13(1):3939
pubmed: 35803923
Am J Med Genet. 1992 Jul 15;43(5):865-71
pubmed: 1642278
Pigment Cell Melanoma Res. 2018 Jul;31(4):466-474
pubmed: 29345414
Nucleic Acids Res. 2001 Jan 1;29(1):308-11
pubmed: 11125122
Sci Rep. 2019 Jan 24;9(1):645
pubmed: 30679655
Hum Genet. 2003 Nov;113(6):502-13
pubmed: 13680365
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Ophthalmic Genet. 2021 Jun;42(3):291-295
pubmed: 33599182
Traffic. 2002 Apr;3(4):237-48
pubmed: 11929605
Nucleic Acids Res. 2020 Jan 8;48(D1):D835-D844
pubmed: 31777943
Pigment Cell Melanoma Res. 2014 Jan;27(1):11-8
pubmed: 24066960
Hum Genet. 2003 Apr;112(4):387-99
pubmed: 12579416
Genome Res. 2018 Nov;28(11):1621-1635
pubmed: 30333196
J Anal Pharm Res. 2020;9(3):81-89
pubmed: 33458560
Sci Rep. 2017 Jun 30;7(1):4415
pubmed: 28667292
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1058-64
pubmed: 19060277
Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444
pubmed: 34791371
J Invest Dermatol. 2011 Jan;131(1):260-2
pubmed: 20861851
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Clin Genet. 2013 Jul;84(1):91-3
pubmed: 23050561
Genome Res. 2003 Aug;13(8):1855-62
pubmed: 12902379
Invest Ophthalmol Vis Sci. 2008 Mar;49(3):868-72
pubmed: 18326704
Hum Mutat. 2021 Oct;42(10):1239-1253
pubmed: 34246199
Mol Vis. 2012;18:38-54
pubmed: 22259223
Br J Ophthalmol. 2019 Sep;103(9):1239-1247
pubmed: 30472657
PLoS One. 2014 Sep 12;9(9):e106656
pubmed: 25216246
Nucleic Acids Res. 2023 Jan 6;51(D1):D977-D985
pubmed: 36350656
PLoS Genet. 2021 May 12;17(5):e1009497
pubmed: 33979322
PLoS One. 2013 Sep 11;8(9):e74307
pubmed: 24040225
Gene Expr. 1991 May;1(2):103-10
pubmed: 1820207
Biochem J. 2001 Apr 15;355(Pt 2):259-69
pubmed: 11284711
Pigment Cell Melanoma Res. 2021 Jan;34(1):10-12
pubmed: 32969584
Am J Med Genet A. 2009 Mar;149A(3):466-9
pubmed: 19208379
Hum Mutat. 2013 Jun;34(6):827-35
pubmed: 23504663
Pigment Cell Melanoma Res. 2014 Jul;27(4):552-64
pubmed: 24739399
N Engl J Med. 2010 May 6;362(18):1686-97
pubmed: 20410501
Genes (Basel). 2021 Mar 30;12(4):
pubmed: 33808351
Bioinformatics. 2015 Nov 1;31(21):3555-7
pubmed: 26139635