Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism.
In this study, we describe three unrelated Japanese patients with hearing loss and symphalangism who were diagnosed with proximal symphalangism (SYM1), atypical multiple synostosis syndrome (atypical SYNS1) and stapes ankylosis with broad thumb and toes (SABTT), respectively, based on the clinical features. Surgical findings in the middle ear were similar among the patients. By next-generation and Sanger sequencing analyses, we identified two novel mutations, c.559C>G (p.P178A) and c.682T>A (p.C228S), in the SYM1 and atypical SYNS1 families, respectively. No pathogenic changes were found in the protein-coding regions, exon-intron boundaries or promoter regions of the NOG, GDF5 or FGF9 genes in the SABTT family. Such negative molecular data suggest there may be further genetic heterogeneity underlying SYNS1, with the involvement of at least one additional gene. Stapedotomy resulted in good hearing in all patients over the long term, indicating no correlation between genotype and surgical outcome. Given the overlap of the clinical features of these syndromes in our patients and the molecular findings, the diagnostic term 'NOG-related-symphalangism spectrum disorder (NOG-SSD)' is advocated and an unidentified gene may be responsible for this disorder.
Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.
Akira
A
Ganaha
Department of Medical Genetics, University of the Ryukyus, Okinawa, Japan.
Tadashi
T
Kaname
Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.
Yukinori
Y
Akazawa
Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.
Teruyuki
T
Higa
Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.
Ayano
A
Shinjou
Department of Medical Genetics, University of the Ryukyus, Okinawa, Japan.
Kenji
K
Naritomi
Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.
Mikio
M
Suzuki
D000328:Adult; D000844:Ankylosis / Q000235:genetics*; D002348:Carpal Bones / Q000002:abnormalities*; D002352:Carrier Proteins / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics*; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics; D005532:Foot Deformities, Congenital / Q000235:genetics*; D056726:Genetic Association Studies; D055428:Growth Differentiation Factor 5 / Q000235:genetics; D006228:Hand Deformities, Congenital / Q000235:genetics*; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013199:Stapes / Q000002:abnormalities*; D013580:Synostosis / Q000235:genetics*; D013639:Tarsal Bones / Q000002:abnormalities*; D055815:Young Adult; D000099176:Noggin Protein
D002352:Carrier Proteins; D051525:Fibroblast Growth Factor 9; D055428:Growth Differentiation Factor 5; D000099176:Noggin Protein; C496459:FGF9 protein, human; C525893:GDF5 protein, human