Novel truncating mutation in TENM3 in siblings with motor developmental delay, ocular coloboma, oval cornea, without microphthalmia

To the Editor, Your journal's recent article describes a second family with autosomal recessive colobomatous microphthalmia and developmental delay (Chassaing et al., 2016), supporting the association of TENM3 mutations with eye abnormalities, and further confirming the earlier report by Aldahmesh, Mohammed, Al-Hazzaa, and Alkuraya (2012). Coloboma refers to an ocular birth defect resulting from abnormal closure of the optic fissure during the fifth to seventh week of embryonic stage in humans (Nakamura, Diehl, & Mohney, 2011). Failure of the fissure to fuse can lead to coloboma of multiple regions of the eye such as iris, zonules and ciliary body, choroid, retina, and optic nerve. Coloboma is a genetically heterogeneous disorder that is often associated with additional ocular features such as microphthalmia, anophthalmia, micro cornea, retinal detachment, and ocular movement disorders. Multisystem abnormalities involving neurological, facial, and urogenital abnormalities have also been described to be associated with optic fissure closure defects, of which neurological abnormalities are relatively common (Skalicky et al., 2013). Odz3, the vertebrate orthologue of Teneurin transmembrane protein 3 encoded by human TENM3 gene, has been well studied for its role in axon guidance, homophilic cell adhesion, and ocular development (Ben-Zur, Feige, Motro, & Wides, 2000; Leamey et al., 2007). So far, four patients from three families manifested with microphthalmia been reported due to bi-allelic mutations in TENM3 (Aldahmesh et al., 2012; Chassaing et al., 2016; Singh, Srivastava, & Phadke, 2018). We now report a fourth family of Indian origin having novel truncating mutation in TENM3 in two similarly affected sisters who manifested with motor developmental delay, eye abnormalities, without microphthalmia. The subjects in the study were consented under clinical protocol 76-HG-0238, approved by the Institutional Review Board of National Human Genome Research Institute. Two siblings born to nonconsanguineous parents were referred for the evaluation of ptosis and developmental delay. Maternal uncle had very severe visual loss and small eyes from history (details are not available). The older child, who is presently 5.5 years old, was initially seen at 2 years and 10 months and presented with global developmental delay. She started to walk at the age of 34 months. On examination, her weight was 19 kg (50th–75th percentile), height was 111 cm (50th percentile) and head circumference was 51 cm (25th–50th percentile) at 5.5 years of age. She had oval shaped cornea with inferonasal iris coloboma bilaterally and ptosis of left eye with a corneal diameter of 11 mm vertically and 9 mm horizontally. Her pupils were keyhole shaped and fundus examination revealed inferomedial retinal coloboma involving the optic discs and fovea (Figure 1a,b). The younger sister who is 5 years old also had oval cornea and history of nystagmus since birth. She had mild motor delay, spoke only few words and was walking with support by 20 months of age. Currently she is 4 years 3 months old and has a weight of 14.5 kg (10–25th percentile), height of 104 cm (50–75th percentile) and head circumference of 47.5 cm (<3rd percentile). She had bilateral partial ptosis, left convergent squint, and oval shaped cornea with inferonasal iris coloboma in both the eyes. Detailed ophthalmological evaluation revealed a corneal diameter of 9 mm vertically and 7 mm horizontally. Like her sister, her pupils were keyhole shaped and fundus examination revealed inferomedial retinal coloboma involving the optic discs but sparing the fovea (Figure 1c,d). The phenotypes of the patients in this study overlap with the earlier reports, including similar ocular defects of iris and retinal coloboma, nystagmus, and esotropia. Neurological problems of delayed milestones, intellectual disability, and speech delay seen in the sibs in this paper are consistent with the earlier patient reported by Chassaing et al., 2016. However, patients in this report did not have microphthalmia and the retinal coloboma was complete in both patients, but spared the fovea in one patient and involving fovea in the other. In addition, we observed ptosis in both patients, while this feature was absent in previously reported patients. A comprehensive clinical comparison of the sibs with previously reported individuals are shown in Table 1. We employed whole exome sequencing to identify the genetic etiology. For exome analysis, we used autosomal recessive mode of inheritance as a filter because the female patients are two similarly affected siblings from a nonconsanguineous family. Further variant filtering strategy used included recessive variants with minor allele frequency < 0.01 in publicly available databases such as ExAC, gnomAD and 1000Genome, and pathogenic in silico predictions according to online prediction tools (SIFT, Polyphen, Mutation Taster, and CADD). Final analysis revealed homozygous variants in two candidate genes: TENM3, NM_001080477. 3: c.1857T>A; p. Cys619* and MBTD1, Received: 3 August 2018 Revised: 17 September 2018 Accepted: 18 September 2018 DOI: 10.1002/ajmg.a. 40658