Orofaciodigital Syndrome Xvi

A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome XVI (OFD16) is caused by homozygous or compound heterozygous mutation in the TMEM107 gene (616183) on chromosome 17p13.

Mutation in the TMEM107 gene can also cause Meckel syndrome-13 (MKS13) and Joubert syndrome-29 (JBTS29); see 617562.

Clinical Features

Shylo et al. (2016) reported a patient with OFD16. The patient had postaxial polydactyly of the hands and feet, multiple tongue cysts, and dysmorphic features, including frontal narrowing, short palpebral fissures, flat nasal bridge, retrognathia, and low-set ears. The patient also had developmental delay, inguinal hernia, and muscle hypotonia associated with motor delay. Other typical ciliopathy-associated features were not present, such as situs abnormalities. Extra digits on both hands had only 2 phalanges, suggesting thumb identity, despite the postaxial location. Brain imaging did not show molar tooth sign (MTS), ruling out Joubert syndrome.

Lambacher et al. (2016) studied 9-year-old twin girls, born of consanguineous Turkish parents, with OFD16. The patients had previously been reported by Darmency-Stamboul et al. (2013) as patients 3 and 4. These girls had delayed psychomotor development with severe cognitive impairment and inability to walk. Other neurologic signs included ataxia, orofacial dyspraxia, fine motor disorder, oculomotor dyspraxia, retinopathy, and apnea/hyperpnea. Additional features included lingual hamartoma, multiple frenula, and postaxial polydactyly of the hands and feet. One had a sacrococcygeal teratoma and the other had a ventricular septal defect. Brain imaging showed multiple infra- and supratentorial abnormalities, including cerebellar and brainstem malformations consistent with MTS, enlarged ventricles, hippocampal malrotation, heterotopia, and temporal lobe hypoplasia.

Inheritance

The transmission pattern of OFD16 in the family reported by Darmency-Stamboul et al. (2013) and Lambacher et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with OFD16, Shylo et al. (2016) identified a homozygous in-frame deletion in the TMEM107 gene (phe106del; 616183.0002). Patient cells showed fewer cilia, and cilia that were formed had a very broad range of lengths compared to controls. The findings indicated that the mutation disrupted cilia formation or maintenance. Patient cilia also showed loss of certain transition zone (TZ) proteins.

In female twins, born of consanguineous parents, with OFD16, Lambacher et al. (2016) identified a homozygous missense mutation in the TMEM107 gene (E45G; 616183.0003). The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or ExAC databases. The E45G mutant protein retained the ability to localize to the transition zone, indicating that the mutation disrupted TMEM107 functions at the transition zone, rather than having a gross effect on TMEM107 localization or stability.