Open AccessA distinctive oral phenotype points to FAM 20A mutations not identified by S anger sequencing
Author(s) -
Poulter James A.,
Smith Claire E. L.,
Murrillo Gina,
Silva Sandra,
Feather Sally,
Howell Marianella,
Crinnion Laura,
Bonthron David T.,
Carr Ian M.,
Watson Christopher M.,
Inglehearn Chris F.,
Mighell Alan J.
Publication year - 2015
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.164
Subject(s) - phenotype , genetics , biology , mutation , dna sequencing , computational biology , gene
Biallelic FAM 20A 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 FAM 20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM 20A 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. CNV seq was used to screen for genomic insertions and deletions. In one family, FAM 20A cDNA screening revealed only a single mutated FAM 20A allele with the wild‐type allele not transcribed. In the second family, CNV detection by whole genome sequencing ( CNV seq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM 20A . This study confirms the link between biallelic FAM 20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM 20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.