Autosomal recessive Leber's hereditary optic neuropathy caused by a homozygous variant in DNAJC30 gene.

Recently, Stenton et al. (2021) described a new, autosomal recessive inheritance pattern of Leber's hereditary optic neuropathy (LHON) caused by missense variants in the DNAJC30 gene. The DNAJC30 c.152A > G, p.(Tyr51Cys) variant was by far the most common variant reported in patients originating from Eastern Europe, therefore, it is believed to be a founder variant in these populations. We report the first two cases of DNAJC30-linked autosomal recessive LHON in a young male and a female originating from Estonia. The patients presented severe loss of central vision and clinical features indistinguishable from mitochondrial LHON. The whole exome sequencing carried out in the male patient and the next-generation sequencing panel in the young female patient identified the same homozygous missense variant in the DNAJC30 gene. Our cases further reinforce the pathogenicity of c.152A > G, p.(Tyr51Cys) DNAJC30 variant causing autosomal recessive LHON. According to the gnomAD database, the allele frequency of this variant in the Estonian population is 0.8%, translating into a prevalence of carriers of 1:60. It is the highest among different gnomAD populations. Applying the Hardy-Weinberg equation, an estimated 92 persons in the Estonian population carry the homozygous variant c.152A > G, p.(Tyr51Cys) in DNAJC30. In patients with LHON, we advise sequencing both the DNAJC30 gene and mitochondrial DNA simultaneously.

Hearing impairment in Estonia: an algorithm to investigate genetic causes in pediatric patients.

PURPOSE: The present study was initiated to establish the etiological causes of early onset hearing loss (HL) among Estonian children between 2000-2009. METHODS: The study group consisted of 233 probands who were first tested with an arrayed primer extension assay, which covers 199 mutations in 7 genes (GJB2, GJB6, GJB3, SLC26A4, SLC26A5 genes, and two mitochondrial genes - 12S rRNA, tRNASer(UCN)). From probands whose etiology of HL remained unknown, DNA analysis of congenital cytomegalovirus (CMV) infection and G-banded karyotype and/or chromosomal microarray analysis (CMA) were performed. RESULTS: In 110 (47%) cases, the etiology of HL was genetic and in 5 (2%) congenital CMV infection was diagnosed. We found mutations with clinical significance in GJB2 (100 children, 43%) and in 2 mitochondrial genes (2 patients, 1%). A single mutation in SLC26A4 gene was detected in 5 probands (2.2%) and was considered diagnostic. In 4 probands a heterozygous IVS2-2A>G change in the SLC26A5 gene was found. We did not find any instances of homozygosity for this splice variant in the probands. CMA identified in 4 probands chromosomal regions with the loss of one allele. In 2 of them we were able to conclude that the found abnormalities are definitely pathogenic (12q13.3-q14.2 and 17q22-23.2 microdeletion), but the pathogenity of 2 other findings (3p26.2 and 1p33 microdeletion) remained unknown. CONCLUSION: This practical diagnostic algorithm confirmed the etiology of early onset HL for 115 Estonian patients (49%). This algorithm may be generalized to other populations for clinical application.

Whole Xp Deletion in a Girl with Mental Retardation, Epilepsy, and Biochemical Features of OTC Deficiency.

Background: Females with a total or partial deletion of the short arm of the X chromosome have variable features of Turner syndrome, but mental retardation (MR) rarely occurs. The haploinsufficiency of deleted genes that escape X-inactivation may explain the occurrence of MR and autism. Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is inherited in an X-linked semi-dominant trait, and the OTC gene maps to Xp21. Methods: We report on a girl with MR, epilepsy and biochemical changes characteristic of OTC deficiency but no identifiable point mutation in the OTC gene. Standard G-banding cytogenetic analysis, whole genome karyotyping, and X-inactivation studies were performed to determine the genetic etiology of the OTC deficiency in the patient. Results: Cytogenetic analysis and molecular karyotyping using SNP array revealed a deletion of the whole short arm of the X chromosome (Xp22.33-p11.1). Inactivation studies also revealed a completely skewed X-inactivation. Conclusion: Our patient presented with MR, epilepsy, and some evidence of reduced OTC activity, but performed genetic studies gave no explanation for this phenotype. We hope that this case report contributes to the understanding of the underlying genetic factors of the manifestation of X-linked disorders in female patients.

A Boy with Holt-Oram Syndrome Caused by Novel Mutation c.1304delT in the TBX5 Gene.

Holt-Oram syndrome (HOS) is an autosomal dominant developmental defect involving preaxial radial ray upper limb deformity and variable cardiac defects. It has been demonstrated that HOS is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 60) of this gene produce preterminal stop codons, which lead to synthesis of a truncated nonfunctional TBX5 protein. The haplo-insufficiency of the TBX5 gene is the most significant cause of HOS. We report on a sporadic patient with clinical features of HOS. Our patient had a cardiac anomaly - a muscular ventricular and atrial septal defect, patent ductus arteriosus and a conduction defect (a first-step atrioventricular block). Upper limb anomalies in our patient were relatively mild and unusual to HOS - distally displaced thumbs, narrow shoulders and hypotrophy of the muscles in the shoulder region. Molecular analysis identified a novel and unusual heterozygous frameshift mutation - c.1304delT (p.Leu435fsX146) - in exon 9 of the TBX5 gene, which is predicted to cause an elongated TBX5 protein with 84 miscoding amino acids and 62 supernumerary C-terminal amino acids. To the best of our knowledge, only one such type of elongation mutation has thus far been reported in the TBX5 gene.