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TBX22 and Tongue-Tie

Tuomas Klockars, M.D., Ph.D., Suvi Kyttanen, S.R.A., Pekka Ellonen, B.Eng.
Objective: To resolve if TBX22 mutations cause isolated tongue-tie in the
Finnish population.
Design: Mutation analysis of the coding region of the TBX22 gene in 50
Finnish isolated tongue-tie patients and 61 control samples.
Results: One putative sequence variation was identified from two male
patients, but whether this represents a polymorphism or causative mutation
remains unknown.
Conclusions: Mutations in the coding region of the TBX22 gene are not a
major cause of ankyloglossia in the Finnish population and do not explain the
sex difference or inheritance of tongue-tie.
KEY WORDS:

ankyloglossia, genetics, mutation, TBX22, tongue tie

Tongue-tie (ankyloglossia) has a prevalence of approximately 4% in the newborn population. An abnormally

tight lingual frenulum causes decreased tongue mobility.
The phenotype varies from absence of significance to rare
complete ankyloglossia. Tongue-tie has been suggested to
cause breastfeeding difficulties, speech disorders, and other
problems related to the limited mobility of the tongue
(Lalakea and Messner, 2003).
The pathogenesis of ankyloglossia is not known. A
significant proportion is inherited as autosomal dominant
trait with incomplete penetrance. Tongue-tie has a male-tofemale ratio of 1.5 to 2.6: 1.0. However, the ratio is 1.2:
1.0 for familial ankyloglossia and 2.9:1.0 for sporadic
ankyloglossia. This difference could be explained by X
chromosomal inheritance (Klockars and Pitkaranta, 2009).
Tongue-tie is usually an isolated condition, but it can be
a feature of certain syndromes. Cleft palate with ankyloglossia (CPX, OMIM 303400) is a semidominant X-linked
disorder caused by mutations in the TBX22 gene. TBX22
encodes a T-box containing transcription factor expressed
in the palatal shelves and tongue during palatogenesis
(Braybrook et al., 2001, 2002). The phenotype varies
widely, from a high-arched palate to a complete cleft of
the secondary palate. Tongue-tie is the sole phenotype in
4% of affected CPX men and in 45% of carrier women. In

addition to CPX, TBX22 mutations have been shown to be

responsible for a significant proportion of nonsyndromic
cleft palate cases (Marcano et al., 2004; Suphapeetiporn
et al., 2007).
Kantaputra et al. (2011) recently investigated whether
ankyloglossia alone or in the presence of other craniofacial
features might be caused by TBX22 mutations. They
reported five putative missense mutations, of which two
were identified from patients with isolated ankyloglossia.
To resolve if TBX22 mutations cause isolated tongue-tie
in the Finnish population, we performed mutation analysis
of the coding region of the TBX22 gene in 50 Finnish
isolated tongue-tie patients and 61 control samples. The
inclusion criterion for affected individuals was previous
tongue-tie operation (frenulotomy or frenuloplasty); the
controls represented the Finnish general population not
known to have ankyloglossia. DNA was extracted from
saliva using the Oragene DNA kit (DNA Genotek Inc.,
Kanata, Ontario, Canada) PCR primers were designed
using The PCR Suite (van Baren and Heutink, 2004) and
genomic sequence of the TBX22 gene (UCSC Genome
Browser, GRCh37 build) to cover the TBX22 exons. The
samples were sequenced by ABI3730xl DNA analyzer
instrument (Applied Biosystems, Life Technologies) and
variant detection was performed with variant analyzer
software (Applied Biosystems, Life Tech., Carlsbad, CA).
The study was approved by the Ethics Committee of the
Helsinki University Central Hospital.
The only putative mutation was a substitution variant
11133g.A found from two male patients (2/50) and as
heterozygous from four female controls (4/61). It represents
a previously reported polymorphism (dbSNP: rs34244923)
resulting in amino acid change from glutamic acid to lysine
(E187K). This change has been observed at a similar
frequency in cleft and control populations (Marcano et al.,
2004). However, considering the location of the mutation it

Dr. Klockars is Specialist in ear, nose and throat diseases, Department

of Otorhinolaryngology, Cleft and Craniofacial Centre, Department of
Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland.
Dr. Kyttanen is Laboratory Analyst and Dr. Ellonen is Head of
Laboratory, Institute for Molecular Medicine Finland, Technology
Centre, Helsinki, Finland.
Submitted May 2011; Accepted August 2011.
Address correspondence to: Dr. Tuomas Klockars, Department of
Otorhinolaryngology, Helsinki University Central Hospital, PL 220, FIN00029 HUS, Finland. E-mail tuomas.klockars@fimnet.fi.
DOI: 10.1597/11-114
378

Klockars et al., TBX22 AND TONGUE-TIE

is possible that this mutation is causative for tongue-tie in

our two male patients.
Kantaputra et al. (2011) demonstrated that TBX22
mutations may cause isolated ankyloglossia in selected
Thai patients. Based on our findings, mutations in the
coding region of the TBX22 gene are not a major cause of
ankyloglossia in the Finnish population and do not explain
the sex-difference or inheritance of tongue-tie.
Acknowledgments. T. Klockars is conducting research on the genetics of
pediatric otorhinolaryngologic diseases with financial support from the
Finska Lakaresallskapet and Wilhelm och Else Stockmanns Stiftelse.

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