Mutation analysis by direct and whole exome sequencing in familial and sporadic tooth agenesis.
Dental agenesis is one of the most common congenital craniofacial abnormalities. Dental agenesis can be classified, relative to the number of missing teeth (excluding third molars), as hypodontia (1 to 5 missing teeth), oligodontia (6 or more missing teeth), or anodontia (lack of all teeth). Tooth agenesis may occur either in association with genetic syndromes, based on the presence of other inherited abnormalities, or as a non-syndromic trait, with both familiar and sporadic cases reported. In this study, we enrolled 16 individuals affected by tooth agenesis, prevalently hypodontia, and we carried out direct Sanger sequencing of paired box 9 (PAX9) and Msh homeobox 1 (MSX1) genes in 9 subjects. Since no mutations were identified, we performed whole exome sequencing (WES) in the members of 5 families to identify causative gene mutations either novel or previously described. Three individuals carried a known homozygous disease mutation in the Wnt family member 10A (WNT10A) gene (rs121908120). Interestingly, two of these individuals were siblings and also carried a heterozygous functional variant in EDAR-associated death domain (EDARADD) (rs114632254), another disease causing gene, generating a combination of genetic variants never described until now. The analysis of exome sequencing data in the members of other 3 families highlighted new candidate genes potentially involved in tooth agenesis and considered suitable for future studies. Overall, our study confirmed the major role played by WNT10A in tooth agenesis and the genetic heterogeneity of this disease. Moreover, as more genes are shown to be involved in tooth agenesis, WES analysis may be an effective approach to search for genetic variants in familiar or sporadic tooth agenesis, at least in more severe clinical manifestations.
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Alessandro
A
Salvi
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Edoardo
E
Giacopuzzi
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Dental Clinic, University of Brescia, I-25123 Brescia, Italy.
Elena
E
Bardellini
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Dental Clinic, University of Brescia, I-25123 Brescia, Italy.
Francesca
F
Amadori
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Lia
L
Ferrari
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Giuseppina
G
De Petro
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Giuseppe
G
Borsani
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Dental Clinic, University of Brescia, I-25123 Brescia, Italy.
Alessandra
A
Majorana
D000293:Adolescent; D000328:Adult; D000848:Anodontia / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods*; D053362:Edar-Associated Death Domain Protein / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D051957:MSX1 Transcription Factor / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051764:PAX9 Transcription Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051153:Wnt Proteins / Q000235:genetics; D055815:Young Adult
C506125:EDARADD protein, human; D053362:Edar-Associated Death Domain Protein; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; C484142:WNT10A protein, human; D051153:Wnt Proteins
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