A Nonsyndromic Autosomal Dominant Oligodontia with A Novel Mutation of P AX 9 -A Clinical and Genetic Report

Abstract

An 8-year-old female patient (proband) reported to the Department of Paediatric Dentistry with a chief complaint of multiple decayed teeth in lower left quadrant of the jaw. The patients past medical history and the family history were not significant. It was patient's first visit to a dentist. Extra-oral examination revealed no abnormalities. Intraoral examination, revealed grossly decayed teeth in relation to 54, 65, 74 and hypo plastic teeth in relation to 64 and 84. The proband (III: 9) Orthopantomographic (OPG) examination revealed agenesis of 18 teeth including third molars. The missing teeth were 12, 13, 15, 17, 18, 22, 23, 25, 27, 28, 33, 35, 37, 38, 43, 45, 47,. The panoramic radiograph also revealed a few developing permanent teeth in relation to 14, 24, 16 and 26. The teeth present were reduced in size, shape. Interviews revealed missing teeth were not extracted and were absence since childhood. Clinical examination of her siblings and the mother showed to have a similar problem. pedigree chartProbands three generation familial pedigree chart was drawn. Probands both parents side pedigree chart was drawn separately. Probands grandparents of both side were no longer lived, so history of missing teeth could not be assessed, excluding them the entire members in the family (25members) were examined clinically. Except for the proband, her siblings and her mother, no one else in the entire family had any history of congenitally missing teeth [Table/ Fig-2].Probands father (II:7) aged 50 years did not have any missing teeth and mother (II:8) of age 38 years had retained teeth in relation to 63, and congenitally missing teeth in relation to 12, 18, 22, 28, 38,. Probands brother (III:7) of age 17 years was examined clinically and radiographically which revealed retained primary teeth in relation to 52, 53, 62, 71, 72, 73, 75, 81, 82, and congenitally missing permanent teeth 12, 13, 18, 22, 28, 31, 32, 33, 35, 38, 41, 42, 43 [ Oligodontia is congenital absence of one or more teeth which has familial abnormality and attributable to various mutations or polymorphisms of genes often associated with malformative syndromes. The present case reports a rare case of non syndromic oligodontia in an 8-year-old girl with missing 14 permanent teeth excluding third molars in mixed dentition. It is a rare finding which has not been frequently documented in Indian children. Mutations in MSX1 and PAX9 have been described in families in which inherited oligodontia characteristically involves permanent incisors, lateral incisors, premolars and molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. This phonotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 revealed a novel mutation in the paired domain of the molecule. The multiple sequence alignment and SNP analysis of the PAX9 exon 2 revealed two mutations.[

PAX9 gene mutations and tooth agenesis: A review

“…This might be taken as an indication that the mutation is causative, but an association study with much larger cohort would be needed before more positive conclusions are made. Thimmegowda et al published a case report for the Ille25Ille mutation but it was not entirely clear which family members were/were not the carriers. The precise locus of the mutation was not given and the corresponding protein structure was not included so the putative impact—if there is any—on hypodontia is hard to evaluate.…”

Patterns of molar agenesis associated with p.P20L and p.R77Q variants in PAX9

“…The heterozygous missense PAX9 variant, c.59C>T (p.Pro20Leu), was observed in Family 1 with four affected members. The p.Pro20Leu was previously reported in two nonsyndromic tooth agenesis families, an Indian family with four affected members [29] and a Japanese family with three affected members [30] (Table 2). In total, there were eight cases identified with the p.Pro20Leu having definite records of third molars.…”

Characterization of PAX9 variant P20L identified in a Japanese family with tooth agenesis

“…Although identical mutation was previously reported in an Indian family with tooth agenesis, since experimental evidences for its causality is lacking [15,16], we decided to investigate this mutation in detail. The variant allele was shared exclusively by the three familial patients as heterozygotes, and not by an unaffected member of the family (Fig 1A).…”

“…An in vitro experiment confirmed the detrimental effect of the mutation on PAX9 activity as a transcription factor. Thimmegowda et al recently reported a haplotype containing both c.59C>T and c.75C>T mutations in the PAX9 coding region in an Indian family with tooth agenesis, which would result in P20L and silent mutation at Ile25 [15,16]. However, they did not refer to the resulting amino acid change, co-segregation of the variant within the family, or the functional implications of the variant.…”