Oral‐facial‐digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum

Abstract

Oral‐facial‐digital syndrome type 1 (OFD1; OMIM# 311200) is an X‐linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post‐mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left‐right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.

Integration of Protein Interactome Networks with Congenital Heart Disease Variants Reveals Candidate Disease Genes

“…This approach yielded 252 proteins in total, which comprised several of the previously reported GATA4 and TBX5 interactors as well as novel interactors (Enane et al, 2017;Padmanabhan et al, 2020;Waldron et al, 2016). Mutations in several of these interactors have been already associated to human or mouse cardiac malformations, highlighting the potential of our approach for disease-gene discovery (Jin et al, 2017;Bouman et al, 2017;Castillo-Robles et al, 2018;Chen et al, 2020;Diets et al, 2019;Dsouza et al, 2019;Ferrante et al, 2006;Gordillo et al, 1993;Hinton et al, 2014;Homsy et al, 2015;Ji et al, 2020;Jones et al, 2012;Lebrun et al, 2018;Lei et al, 2012;Lepore et al, 2006;Maitra et al, 2010;Parisot et al, 2010;Pierpont et al, 2018;Takeuchi et al, 2011;Thienpont et al, 2010;Van Dijck et al, 2019;Wilczewski et al, 2018) (Figure 1B and1C, Figure S2A and S2B…”

Patient with Regional Missing Teeth Encountered with Syndactylia-Clinodactilia and Tongue Anomalies

“…Possible syndromes include; Oculodentodigital dysplasia (ODDD), a rare congenital autosomal dominant disorder characterized by abnormalities of the eyes, limbs, and teeth, Oro-facial-digital syndrome type 1 syndrome (OFDS) characterized by various degrees of bradydactyla, syndactic and clinodactyly, and mutation in CXORF5 gene between finger 2 and finger 5 or with digital anomalies and malformed ears, as well as with syndromes such as Lacrimo-auriculo-dento-digital (LADD). [3][4][5] Regional odontodysplasia is a relatively uncommon condition that affect odontogenic structures. [6][7][8][9][10] Diagnosis is based on clinical and radiographic findings.…”

“…Type 1 syndrome is considered, but the possibility that the syndrome is lethal when seen in men has almost eliminated the possibility. 4 In such cases, it is important to have a genetic diagnosis. However, genetic testing has not been conducted on whether the parent is not convinced of the necessity of genetic testing or not.…”

Indian child with novel variant in OFD1 gene

“…This X‐linked form of OFD: OFD1 manifests primarily in the females as it is lethal because of severe phenotype in the affected males (Online Mendelian Inheritance in Man [OMIM], 2020). Severe cardiac defect like hypoplastic left heart can cause fetal demise in affected males (Bouman et al, 2017). The CNS malformations are common; and renal cysts are seen in around 60% of affected cases (Prattichizzo et al, 2008).…”