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A Comprehensive Genetic Analysis of Slovenian Families with Multiple Cases of Orofacial Clefts Reveals Novel Variants in the Genes IRF6, GRHL3, and TBX22
被引:3
|作者:
Slavec, Lara
[1
,2
]
Gersak, Ksenija
[1
,3
]
Eberlinc, Andreja
[4
]
Hovnik, Tinka
[5
,6
]
Lovrecic, Luca
[3
,7
]
Mlinaric-Rascan, Irena
[2
]
Kuzelicki, Natasa Karas
[2
]
机构:
[1] Univ Med Ctr Ljubljana, Div Gynaecol & Obstet, Res Unit, Ljubljana 1000, Slovenia
[2] Univ Ljubljana, Fac Pharm, Dept Clin Biochem, Ljubljana 1000, Slovenia
[3] Univ Ljubljana, Fac Med, Dept Gynaecol & Obstet, Ljubljana 1000, Slovenia
[4] Univ Med Ctr Ljubljana, Dept Maxillofacial & Oral Surg, Ljubljana 1000, Slovenia
[5] Univ Med Ctr Ljubljana, Univ Childrens Hosp, Clin Inst Special Lab Diagnost, Ljubljana 1000, Slovenia
[6] Univ Ljubljana, Inst Biochem & Mol Genet, Fac Med, Ljubljana 1000, Slovenia
[7] Univ Med Ctr Ljubljana, Clin Inst Genom Med, Ljubljana 1000, Slovenia
关键词:
genetics;
family study;
non-syndromic orofacial cleft;
Van der Woude syndrome;
X-linked cleft palate with or without ankyloglossia;
IRF6;
GRHL3;
TBX22;
whole exome sequencing;
WOUDE-SYNDROME;
ORAL CLEFTS;
CANDIDATE GENES;
CAUSE VAN;
MUTATIONS;
PALATE;
DATABASE;
LIP;
PREDICTION;
IDENTIFICATION;
D O I:
10.3390/ijms24054262
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1; VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only minor clinical signs in addition to OFC and are sometimes difficult to differentiate from nsOFCs. We recruited 34 Slovenian multi-case families with apparent nsOFCs (isolated OFCs or OFCs with minor additional facial signs). First, we examined IRF6, GRHL3, and TBX22 by Sanger or whole exome sequencing to identify VWS and CPX families. Next, we examined 72 additional nsOFC genes in the remaining families. Variant validation and co-segregation analysis were performed for each identified variant using Sanger sequencing, real-time quantitative PCR and microarray-based comparative genomic hybridization. We identified six disease-causing variants (three novel) in IRF6, GRHL3, and TBX22 in 21% of families with apparent nsOFCs, suggesting that our sequencing approach is useful for distinguishing syOFCs from nsOFCs. The novel variants, a frameshift variant in exon 7 of IRF6, a splice-altering variant in GRHL3, and a deletion of the coding exons of TBX22, indicate VWS1, VWS2, and CPX, respectively. We also identified five rare variants in nsOFC genes in families without VWS or CPX, but they could not be conclusively linked to nsOFC.
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页数:19
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