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Expanding the phenotypic and genotypic spectrum of TENM3-related syndromic microphthalmia
Ozan Vural1, Tarik Duzenli1, Sengul Özdek2
1Faculty of Medicine, Department of Medical Genetics, Gazi University, Ankara, Türkiye.
Purpose:
To expand the phenotypic and genotypic spectrum of syndromic microphthalmia 15 (MCOPS15; OMIM #615145), a rare disorder caused by biallelic pathogenic variants in teneurin transmembrane protein 3.
Methods:
We report two affected siblings with syndromic microphthalmia and global developmental delay. Detailed ophthalmological, neurodevelopmental, and systemic clinical evaluation was performed. Exome sequencing was carried out in the elder brother, with variant classification per ACMG 2015 guidelines, followed by Sanger segregation analysis in the younger brother.
Results:
Both siblings harbored a novel homozygous frameshift variant, c.6417_6420del (p.Thr2140Phefs*7), in TENM3 (NM_001080477.4), classified as likely pathogenic (PVS1, PM2). The elder brother presented with microphthalmia, intellectual disability, choroidal coloboma, nystagmus, nephrolithiasis, and hypospadias; the younger brother showed more pronounced global developmental delay, milder ocular involvement, pes planus, and a double external urethral orifice.
Conclusions:
These findings expand the known spectrum of TENM3-related microphthalmia. Genitourinary anomalies, not consistently described in prior reports, may represent true phenotypic variability, incomplete evaluation, or selective reporting in series focused on the ocular and neurodevelopmental phenotype.
Insights
This study identifies a new TENM3 gene variant in siblings with syndromic microphthalmia and developmental delay. The findings broaden the understanding of MCOPS15, highlighting potential genitourinary anomalies.
Area of Science:
- Genetics
- Ophthalmology
- Developmental Biology
Background:
- Syndromic microphthalmia 15 (MCOPS15) is a rare genetic disorder.
- It is caused by pathogenic variants in the TENM3 gene.
- Expanding the known spectrum of MCOPS15 is crucial for diagnosis and management.
Purpose of the Study:
- To expand the phenotypic and genotypic spectrum of MCOPS15.
- To characterize a novel TENM3 variant and its associated clinical features.
Main Methods:
- Clinical evaluation of two siblings with syndromic microphthalmia and global developmental delay.
- Exome sequencing to identify genetic variants.
- Variant classification using ACMG 2015 guidelines and Sanger sequencing for confirmation.
Main Results:
- A novel homozygous frameshift variant (c.6417_6420del) in TENM3 was identified in both siblings.
- The variant was classified as likely pathogenic.
- Phenotypic features included microphthalmia, intellectual disability, choroidal coloboma, nystagmus, nephrolithiasis, hypospadias, and genitourinary anomalies.
Conclusions:
- The identified TENM3 variant expands the known spectrum of MCOPS15.
- Genitourinary anomalies may be part of the phenotypic variability in TENM3-related microphthalmia.
- Further research is needed to fully understand the genotype-phenotype correlations.
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