Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS) is an extremely rare autosomal dominant genetic disease caused by disruptive pathogenic variants in CTBP1. There are merely 12 cases reported to have pathogenic variants in the CTBP1 gene. Here, we report the first case with HADDTS in the Middle-Eastern population. In the present study, wholeexomesequencing was deployed to identify the variant(s) causing this condition. Subsequently, Sanger sequencing was performed to confirm the variant. The clinical evaluation of the patient is written according to the thoroughly carried out examinations and clinical investigations. A novel single frameshift pathogenic variant in CTBP1 (NM_001328.3:c.1315_1316delCA, p.Gln439ValfsTer84) wasidentified as the cause for HADDTS in the proband. Our findings enhance the knowledge of poorly studied CTBP1. The newly reported patient is phenotypically different in comparison to the previously reported cases. He has no sign of hypotonia, difficulty in walking or standing.

Pathogenic variants in MCM2 could result in mild to severe sensorineural hearing loss in the affected individuals (deafness, autosomal dominant 70; DFNA70; OMIM: 616968), an extremely rare autosomal dominant progressive disorder. Here, we report a novel missense variant (NM_004526:c.388C>T, p.R130C; Clinvar: SCV002072508) in MCM2 in an Iranian family identified by whole-exome sequencing and confirmed by Sanger sequencing. The heterozygous variant (NM_004526:c.388C>T, p.R130C) in MCM2 was identified in the proband and his mother. The proband is a nine-year-old male born to nonconsanguineous parents. The proband was characterized by nonsyndromic hearing loss, while his mother showed a mild form of the disorder. This study reports the second disease-causing variant in MCM2 in the world and confirms that hearing loss arising from variants in MCM2 is nonsyndromic. Nevertheless, as was reported in the previous family, phenotype could vary among the patients with the same variant.

Pathogenic variants in OTOF cause auditory neuropathy spectrum disorder (ANSD), namely prelingual nonsyndromic ANSD and temperature-sensitive ANSD (TS-ANSD). All study subjects provided blood sample for genetic analysis and sequencing. Wholeexome sequencing was carried out to identify the causative pathogenic variant. RNAwas extracted to analyse the messenger RNA (mRNA) resulting from the transcription of OTOF. Here, we identified a family with OTOF-related ANSD. This disorder was caused by an intronic mutation in OTOF (NM_194248: c.2406?4A[G). In further analysis, we proved that this variant causes a splicing defect resulting in theomission of exon 20 from the mRNA transcribed from OTOF. In this study, we demonstrated that the variant is four nucleotides away from the conventional splicing site, and our findings suggest that splicing mechanisms need to be better understood, as well as how neighbouring regions may impact splicing.