Spectrum of genetic variants in 306 patients with non-syndromic hearing loss from Croatia.

AIM: To determine the spectrum and frequency of disease-causing variants in patients with non-syndromic hearing loss (NSHL) and to investigate the diagnostic yield of the applied genetic methods. METHODS: The study enrolled 306 unrelated patients with childhood-onset, mild-to-profound NSHL referred to Children's Hospital Zagreb for genetic testing between March 2006 and October 2023. The GJB2 variants were analyzed with the multiplex ligation-dependent probe amplification method and Sanger sequencing of the coding region of the GJB2 gene. In 21 patients negative for GJB2 biallelic variants, clinical exome sequencing (CES) was performed. RESULTS: Among 234 disease-associated GJB2 alleles detected, 19 were clinically relevant, of which 18 were reported as pathogenic/likely pathogenic. The c.35delG variant accounted for 73.5% of the mutated alleles. More than half of the patients with biallelic GJB2 variants (64/110, 58.2%) were 35delG homozygotes. Seventeen non-GJB2 variants were found in 10 genes (TECTA, NOG, SLC26A4, PCDH15, TMPRSS3, USH2A, GATA3, MYO15A, SOX10, COL2A1) in 11 participants, and 5 variants (in TECTA, NOG, PCDH15, and SOX10) were novel (29.4%). CONCLUSION: We were able to elucidate the genetic cause of hearing loss in 121 patients, with an overall diagnostic rate of 39.5%. The c.35delG was the most common variant. CES allowed us to diagnose almost half of the patients with HL; to distinguish NSHL from the syndromic form of HL in cases where the phenotype was unclear or where symptoms were absent from an early age; and to discover novel variants.

Clinical relevance of the TECTA c.6183G>T variant identified in a family with autosomal dominant hearing loss: a case report.

Missense variants in the α-tectorin gene (TECTA) cause autosomal dominant (DFNA8/A12) non-syndromic hearing loss (ADNSHL) and account for a considerable number of ADNSHL cases. According to genotype-phenotype correlation studies, missense variants in the zona pellucida (ZP) domain of α-tectorin predominantly cause mid-frequency HL. Here, we report on clinical exome sequencing results in a large family with early-onset, sensorineural, moderate-to-severe mid-frequency HL. We identified one heterozygous c.6183G>T variant near the ZP domain of TECTA segregating in five family members. This variant was previously reported as a variant of uncertain significance in a family with ADNSHL. On the basis of specific segregation in the currently studied family and the general guidelines of the American College of Medical Genetics and Genomics, we argue that the TECTA c.6183G>T variant should be considered a likely pathogenic cause of ADNSHL. This report adds to the knowledge on the rare c.6183G>T missense variant, which affects the immediate vicinity of the ZP domain in TECTA. Our findings highlight the importance of clinical evaluation in patients with familial HL and of studying family segregation when assessing the pathogenicity of a variant.

Neurodevelopmental disorder caused by an inherited novel KMT5B variant: case report.

Neurodevelopmental disorders are a large group of disorders that affect ~ 3% of children and represent a serious health problem worldwide. Their etiology is multifactorial and includes genetic, epigenetic, and environmental causes. Mounting evidence shows the importance of genetic causes, especially genes involved in the central nervous system development. As recently discovered, the KMT5B gene is related to abnormal activities of the enzymes that regulate histone activity and gene expression during brain development. Pathogenic KMT5B gene variants lead to autosomal dominant, intellectual developmental disorder 51 (OMIM # 617788). Also, reports on patients with additional features suggest that the KMT5B gene alterations lead to multisystem involvement. Here, we report on a male patient with a severe neurodevelopmental disorder caused by a novel KMT5B gene variant inherited from his mother. The patient had severe intellectual disability, absent speech, marked autistic behavior, attention deficit hyperactivity disorder, and different clinical features, including thoracic scoliosis, dysmorphic facial features, and tall stature. In contrast, his mother, with the same KMT5B variant, had mild intellectual disability and some autistic traits (stereotype hand movement). We elucidated pathogenetic mechanisms that could influence phenotype characteristics. Our findings emphasize the importance of a comprehensive clinical and molecular approach to these patients in order to provide optimal health care.

Trends in the treatment of undescended testes: a pediatric tertiary care center experience from Croatia.

Objective: Undescended testes (UDT) is the most common anomaly of the male genitourinary tract. The guidelines suggest that orchidopexy in congenitally UDT should be performed between 6 months and 18 months of age, while in acquired UDT, orchidopexy should be performed before puberty. Delay in treatment increases the risk of cancer and infertility. The main aim of this study was to determine whether we meet international standards in the treatment of UDT. Methods: The present study included all boys who underwent orchidopexy either due to congenital or acquired UDT in 2019 (from January 1 to December 31). For each group, laterality, location, associated anomalies, premature birth and in how many cases ultrasound was applied were determined. Additionally, for each group, the types of surgery, the number of necessary reoperations, and in how many cases atrophy occurred were determined. Finally, ages of referral, of clinical examination, and of orchidopexy were determined. Results: During this period, 198 patients with 263 UDT underwent orchidopexy. The median time of orchidopexy for the congenital group was 30 months, while that for the acquired group was 99 months. In the congenital group up to 18 months of age, orchidopexy was performed in 16 (16%) boys, while in the acquired group up to 13 years of age, orchidopexy was performed in 95 (96.94%) boys. Conclusion: Given the well-known risks of late treatment of UDT, orchidopexy needs to be performed much earlier, especially in the congenital group.