title: A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing.
abstract: 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 FAM20A mutations 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.
authors.affiliation: Section of Ophthalmology and Neuroscience University of Leeds Leeds United Kingdom.
authors.forename: James A
authors.identifier: 0000-0003-2048-5693
authors.initials: JA
authors.lastname: Poulter
authors.affiliation: Section of Ophthalmology and Neuroscience University of Leeds Leeds United Kingdom.
authors.forename: Claire E L
authors.initials: CE
authors.lastname: Smith
authors.affiliation: School of Dentistry University of Costa Rica San Pedro Costa Rica.
authors.forename: Gina
authors.initials: G
authors.lastname: Murrillo
authors.affiliation: Biology Molecular Cellular Centre (CBCM) University of Costa Rica San Pedro Costa Rica.
authors.forename: Sandra
authors.initials: S
authors.lastname: Silva
authors.affiliation: Paediatric Nephrology Leeds Teaching Hospitals NHS Trust Leeds United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Feather
authors.affiliation: Paediatric Nephrology National Children's Hospital San Jose Costa Rica.
authors.forename: Marianella
authors.initials: M
authors.lastname: Howell
authors.affiliation: Yorkshire Regional Genetics ServiceLeeds Teaching Hospitals NHS TrustLeedsUnited Kingdom; Section of GeneticsSchool of MedicineUniversity of LeedsLeedsUnited Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Crinnion
authors.affiliation: Yorkshire Regional Genetics ServiceLeeds Teaching Hospitals NHS TrustLeedsUnited Kingdom; Section of GeneticsSchool of MedicineUniversity of LeedsLeedsUnited Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: Section of Genetics School of Medicine University of Leeds Leeds United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: Yorkshire Regional Genetics ServiceLeeds Teaching Hospitals NHS TrustLeedsUnited Kingdom; Section of GeneticsSchool of MedicineUniversity of LeedsLeedsUnited Kingdom.
authors.forename: Christopher M
authors.identifier: 0000-0003-2371-1844
authors.initials: CM
authors.lastname: Watson
authors.affiliation: Section of Ophthalmology and Neuroscience University of Leeds Leeds United Kingdom.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: Section of Ophthalmology and NeuroscienceUniversity of LeedsLeedsUnited Kingdom; Department of Oral MedicineSchool of DentistryUniversity of LeedsLeedsUnited Kingdom.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mighell
keywords: Amelogenesis imperfecta; CNVseq; FAM20A; enamel renal syndrome