A Novel Mutation in the OFD1 Gene Causes Oral-Facial-Digital Syndrome Type 1 in an Iranian Family

Introduction: Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene which can result in embryonic male lethalityCase Report: Patient 1 (III-VII) The first patient was a 9-year-old girl with a birth weight of 3200 g who was born to a family with non-consanguineous parents at 37 wk gestation, because of the fourth pregnancy. Facial abnormalities that could be seen in the patient were dolichocephaly, macrocephaly (54.3 cm- 88 percentile), saddle nose deformity, low set ears, downslant palpebral fissures, and thin hair and eyebrows. Patient 2 (III-III) She had the following abnormalities: dolichocephaly, macrocephaly (51 cm- 66 percentile), multiple and malaligned dentition, cleft lip and palate, asymmetric, bifid and lobulated tongue, macroglossia, multiple hyperplastic frenulum, ankyloglossia, low set ears, downslant palpebral fissures, and thin hair and eyebrows. Mother of the patients (II-IV) The mother of patients 1 and 2 was 29 yr old. She had ah history of five abortions of malformed male fetuses (III-I, III-II, III-IV, III-V and III-VI). The abortions of all male fetuses happened during her third month of pregnancy. She was born with bifid tongue that was surgically repaired. In addition, her dry and thin hair is remarkableMethod: We extracted genomic DNAs from the peripheral blood samples using the ReliaPrep™ kit (Blood gDNA Miniprep System, Promega). The mutational hotspot within 8 exons of OFD1 (including exons 2, 3, 7, 8, 9, 12, 13 and 16) were amplified based on standard protocols. Primer sequences are available upon request. Then, the study employed 3730 DNA Analayser and BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems) for sequencing of the PCR products in both directions.Results: Our genetic studies identified a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 leading to a frame shift (p.Arg654X) in two patients and their mother. The mutation has not been previously reported, nor is present in The NHLBI Exome Sequencing Project Exome Variant Server (September 2013), Complete Genomics (February 2012), dbSNP (134–137), 1000 Genomes (May 2012) and Exome Aggregation Consortium (ExAC), Cambridge, MA and as it was expected it was absent in the father and the brother of mother Conclusions: We identified a novel truncating mutation in OFD1 in three female members of a family displaying variable symptoms and severity of clinical manifestation of OFDS type 1. As observed in previous cases with OFD1, phenotypic variability even within a family is possibly a rule rather than the exception. Hence, this report emphasizes importance as well as the challenges of genetic counseling for OFD1 patients and their relatives. In cases of OFDS, thorough physical examination, collecting the family history and genetic screening of the affected individuals and their female relatives, along with monitoring of renal function are mandatory.

کلیدواژه ها:

OFD1 ، Oral-facial-digital syndrome ، X-linked dominant ، Miscarriage ، Ciliopathy