Table 1: Checked genes related to microphthalmia (AD: Autosomal Dominant, AR: Autosomal Recessive, XLD: X-linked Dominant)

The proband described in this study had clinical manifestations such as mild intellectual disability, bilateral decrease in the ocular globe size, and coloboma, which conform to the diagnosis of non-syndromic bilateral colobomatous microphthalmia. Both parent’s detailed ocular examination was normal. The patient’s parents were normal based on eye examinations performed by a specialist physician.

Sanger validation of the TENM3 gene endorsed the fact that the proband had a homozygous c.5069-1G>C variation (Figure 2). The detected homozygous canonical splice site variant in theTENM3 gene has not been reported up to now for its pathogenicity. However, based on various silico computational analyses mentioned in the Varsome database for pathogenicity scores such as BayesDel addAF, BayesDel noAF, DANN, EIGEN, EIGEN PC, FATHMM-MKL, and Mutation Taster, the variant has a deleterious effect on the gene or gene product(s). Founded on the American College of Medical Genetics and Genomics (ACMG) guideline, this variant can be categorized as pathogenic (PVS1: Very Strong, PM2: Moderate, PP3: Supporting).

Congenital malformations of the eye are one of the main reasons for blindness and ocular morbidity in childhood. Considering almost 4000 genetic disorders and syndromes, which have an effect on humans, at least 33% affects the eye [23].

The TENM3 gene encodes the Teneurin transmembrane protein 3 in humans, which has been investigated for its role in the development of the eye, adhesion of homophilic cells, and axon guidance [24], [25]. This protein consists of 2699 amino acids (NP_001073946.1). The family of Teneurin includes 4 distinct types of transmembrane dimeric proteins (TENM1-4 ) [26].

It has been shown that the TENM3 gene expresses in the nervous system and a restricted set of mesoderm-derived tissues. It has been suggested that the TENM3 gene plays a vertebrate orthologue conserved role in ocular development as it was detected to be mainly enriched in the optic stalk. [24] Due to the strong brain teneurins expression in neuronal subpopulations and the positional mapping, there could be a connection to intellectual disability, especially during development [27].

To the best of our knowledge, 7 mutations have been reported in theTENM3 gene in 6 unrelated families, 6 of which are ascribed eye anomalies. Our report would be the 7^th MO and coloboma causative mutation in this gene [2], [26], [28]–[31]. You can see the information of these seven mutations in table 2.

The first mutation of the TENM3 gene was reported in two siblings of a consanguineous family. These brothers were both suffering from isolated bilateral microphthalmia, microcornea, and retinal and iris coloboma. The homozygous c.2083dup variant was detected in them while their parents were unaffected carriers [28].

A homozygous splice mutation (c.2968-2A>T) in theTENM3 gene was detected in a son of 9 from a consanguineous family. The proband was affected by bilateral colobomatous microphthalmia and developmental delay [2].

Two novel compound heterozygous variations (c.4046C>G and c.7687C>T) in the TENM3 gene was found in a boy of 6, with eye anomalies and intellectual disability [29].

Another novel mutation (c.1857T>A) in the homozygous state in the TENM3 gene has been reported in two sisters from nonconsanguineous parents. These siblings did not have microphthalmia, but they had ptosis, developmental delay, and iris coloboma [26].

Feldman et al. found a homozygous c.7994A>C variant in theTENM3 gene in 3 affected patients of a 4 generation family who were suffering from developmental dislocation of the hip [30].

In addition, Islam et al. identified c.1558C>T (a pathogenic homozygous variant) in the TENM3 gene in a patient who was suffering from cataracts, bilateral iris, and chorioretinal colobomas microphthalmia [31].

Therefore, it seems that the TENM3 gene is vital in the eye development process, and pathogenic variations of this gene could bring about MAC ocular malformations spectrum and intellectual disability. The detected mutation in our case, c.5069-1G>C, has not been reported before and can be considered as a novel mutation. The present finding can be used for genetic diagnosis and detection of carriers in the family and other patients with similar disease manifestations.