GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome
Carregando...
Citações na Scopus
70
Tipo de produção
article
Data de publicação
2019
Editora
CELL PRESS
Indexadores
Título da Revista
ISSN da Revista
Título do Volume
Autores
LACROIX, Amy J.
STABLEY, Deborah
SAHRAOUI, Rebecca
ADAM, Margaret P.
MEHAFFEY, Michele
KERNAN, Kelly
MYERS, Candace T.
FAGERSTROM, Carrie
ANADIOTIS, George
AKKARI, Yassmine M.
Autor de Grupo de pesquisa
Univ Washington Ctr Mendelian Geno
Editores
Coordenadores
Organizadores
Citação
AMERICAN JOURNAL OF HUMAN GENETICS, v.104, n.1, p.35-44, 2019
Resumo
Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.
Palavras-chave
Referências
- Al-Jezawi NK, 2017, AM J MED GENET A, V173, P1773, DOI 10.1002/ajmg.a.38244
- Baratela WAR, 2012, AM J MED GENET A, V158A, P1815, DOI 10.1002/ajmg.a.35445
- Brisson D, 2002, CLIN GENET, V62, P220, DOI 10.1034/j.1399-0004.2002.620306.x
- Bui C, 2014, AM J HUM GENET, V94, P405, DOI 10.1016/j.ajhg.2014.01.020
- Dashnow H, 2018, DETECTING TANDEM REP, V19, P121
- Ehtesham N, 2002, AM J HUM GENET, V71, P947, DOI 10.1086/342669
- Faust I, 2014, BMC GENET, V15, DOI 10.1186/s12863-014-0129-0
- Favaro FP, 2014, AM J HUM GENET, V94, P120, DOI 10.1016/j.ajhg.2013.11.020
- GOLDBERG YP, 1993, NAT GENET, V5, P174, DOI 10.1038/ng1093-174
- Guo L, 2017, J HUM GENET, V62, P447, DOI 10.1038/jhg.2016.143
- Hannes FD, 2009, J MED GENET, V46, P223, DOI 10.1136/jmg.2007.055202
- HANSEN RS, 1992, HUM MOL GENET, V1, P571, DOI 10.1093/hmg/1.8.571
- Hauer NN, 2018, GENET MED, V20, P630, DOI 10.1038/gim.2017.159
- Heinzen EL, 2010, AM J HUM GENET, V86, P707, DOI 10.1016/j.ajhg.2010.03.018
- Jamsheer A, 2016, J HUM GENET, V61, P577, DOI 10.1038/jhg.2016.30
- Krumm N, 2012, GENOME RES, V22, P1525, DOI 10.1101/gr.138115.112
- La Spada AR, 2010, NAT REV GENET, V11, P247, DOI 10.1038/nrg2748
- Lalioti MD, 1999, HUM MOL GENET, V8, P1791, DOI 10.1093/hmg/8.9.1791
- NANCARROW JK, 1995, HUM MOL GENET, V4, P367, DOI 10.1093/hmg/4.3.367
- NANCARROW JK, 1994, SCIENCE, V264, P1938, DOI 10.1126/science.8009225
- Prydz K, 2000, J CELL SCI, V113, P193
- Schreml J, 2014, HUM GENET, V133, P29, DOI 10.1007/s00439-013-1351-y
- Silveira C, 2016, AM J MED GENET A, V170, P3043, DOI 10.1002/ajmg.a.37858
- Ullmann R, 2007, HUM MUTAT, V28, P674, DOI 10.1002/humu.20546
- van Koningsbruggen S, 2016, AM J MED GENET A, V170, P510, DOI 10.1002/ajmg.a.37453
- Yang YP, 2013, NEW ENGL J MED, V369, P1502, DOI 10.1056/NEJMoa1306555