A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing
Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20Amutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.
Keywords:
Amelogenesis imperfecta, CNVseq, enamel renal syndrome, FAM20A
Autoři:
James A. Poulter 1; Claire E. L. Smith 1; Gina Murrillo 2; Sandra Silva 3; Sally Feather 4; Marianella Howell 5; Laura Crinnion 6,7; David T. Bonthron 6,7; Ian M. Carr 7; Christopher M. Watson 6,7; Chris F. Inglehearn 1; Alan J. Mighell 1,8,*
Působiště autorů:
Section of Ophthalmology and Neuroscience, University of Leeds, Leeds, United Kingdom
1; School of Dentistry, University of Costa Rica, San Pedro, Costa Rica
2; Biology, Molecular Cellular, Centre (CBCM), University of Costa Rica, San Pedro, Costa Rica
3; Paediatric Nephrology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
4; Paediatric Nephrology, National Children's Hospital, San Jose, Costa Rica
5; Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
6; Section of Genetics, School of Medicine, University of Leeds, Leeds, United Kingdom
7; Department of Oral Medicine, School of Dentistry, University of Leeds, Leeds, United Kingdom
8
Vyšlo v časopise:
Molecular Genetics & Genomic Medicine 2015; 3(6)
Kategorie:
Original Research
prolekare.web.journal.doi_sk:
https://doi.org/10.1002/mgg3.164
© 2015 University of Pretoria. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Souhrn
Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20Amutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.
Keywords:
Amelogenesis imperfecta, CNVseq, enamel renal syndrome, FAM20A
Zdroje
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Štítky
GenetikaČlánok vyšiel v časopise
Molecular Genetics & Genomic Medicine
2015 Číslo 6
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