Contents lists available at ScienceDirect Archives of Oral Biology journal homepage: www.elsevier.com/locate/archoralbio Research paper Variable expressivity of TCTEX1D2 mutations and a possible pathogenic link of molar-incisor malformation to ciliary dysfunction Johannes Zschocke a , Anna Schossig a , Dieter D. Bosshardt b , Daniela Karall c , Rudolf Glueckert d , Ines Kapferer-Seebacher e, ⁎ a Division of Human Genetics, Medical University Innsbruck, Peter-Mayr-Strasse 1, 6020 Innsbruck, Austria b Robert K. Schenk Laboratory of Oral Histology, University of Bern, Freiburgstrasse 7, 3010 Bern, Switzerland c Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria d Department of Otolaryngology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria e Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria ARTICLE INFO Keywords: Jeune syndrome TCTEX1D2 Dental development Odontogenesis Molar-incisor-malformation ABSTRACT Objective: Clarification of the molecular basis of a ciliopathy associated with molar-incisor malformation in a consanguineous Turkish family. Design: Full dental and clinical examinations, histologic analysis, comprehensive genetic analyses including exome sequencing, ciliary function tests and transmission electron microscopy of ciliary biopsies in the surviving patient. Results: Two siblings had situs inversus and complex heart defects suggestive of ciliary dysfunction. The affected girl who died in utero showed severe chest abnormalities compatible with Jeune syndrome which were not present in the affected boy. Dental investigations in the boy showed typical signs of molar-incisor-malformation. Exome sequencing identified a homozygous intragenic deletion in TCTEX1D2 which is predicted to completely remove protein function. Ciliary function tests and electron microscopy showed mild irregularities of motile cilia such as compound cilia and loss of membranes. Conclusions: Our findings support the suggestion that TCTEX1D2 mutations have variable expressivity and may be associated with disturbances of embryonic development caused by both, ciliary signaling and motile dysfunction. The presence of molar-incisor-malformation in the living patient raises the possibility of a pathogenetic link of this rare dental anomaly to ciliary dysfunction during tooth development at least in some individuals. 1. Introduction Molar-incisor-malformation (MIM) is a recently described dental anomaly of the permanent first molars, deciduous second molars, and permanent maxillary central incisors (Lee et al., 2014). Affected molars show normal crowns with a constricted cervical region, and thin and short roots, whereas the affected maxillary central incisors exhibit a hypoplastic enamel notch near the cervical third of the clinical crown (Lee et al., 2014, 2015). The pathogenic basis of MIM is unclear; an epigenetic disturbance linked to CNS-related systemic diseases or medication at around age 1 to 2 years has been discussed (Lee et al., 2014). Here we report MIM in a patient with situs inversus, intellectual disability, a deceased sister with Jeune syndrome, and a homozygous loss of function mutation in TCTEX1D2. 2. Case report Patient 1, a 9-year-old boy of Turkish origin with intellectual disability, was referred to the Department of Operative and Restorative Dentistry, Medical University of Innsbruck for dental treatment under general anaesthesia. The boy was born at term by caesarean section (due to breech position) after an uneventful preg- nancy. The first three months of life he was under intensive care and underwent several operations because of a complex heart defect with http://dx.doi.org/10.1016/j.archoralbio.2017.04.009 Received 4 February 2016; Received in revised form 12 April 2017; Accepted 17 April 2017 ⁎ Corresponding author. E-mail addresses: johannes.zschocke@i-med.ac.at (J. Zschocke), anna.schossig@i-med.ac.at (A. Schossig), dieter.bosshardt@zmk.unibe.ch (D.D. Bosshardt), daniela.karall@i-med.ac.at (D. Karall), rudolf.glueckert@i-med.ac.at (R. Glueckert), ines.kapferer@i-med.ac.at (I. Kapferer-Seebacher). Abbreviations: JADT, Jeune asphyxiating thoracic dystrophy; TCTEX1D2, TCTEX1 domain containing protein 2; SRPS, short-rib polydactyly syndromes; IFT, intraflagellar transport; MIM, molar-incisor-malformation Archives of Oral Biology 80 (2017) 222–228 0003-9969/ © 2017 Elsevier Ltd. All rights reserved. MARK