Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.

Background: Mycoplasmas (Mycoplasma spp. and Ureaplasma spp.) are sexually transmitted organisms found primarily in the human urogenital microbiota. These microorganisms are frequently associated with some diseases including non-gonococcal urethritis, vaginosis, pregnancy complications, prenatal infections, systemic infections and infertility.

Keutel syndrome is caused by mutations in the matrix gamma-carboxyglutamic acid (MGP) gene (OMIM 154870) and is inherited in an autosomal recessive fashion. It is characterized by brachydactyly, pulmonary artery stenosis, a distinctive facial phenotype, and cartilage calcification. To date, only 36 cases have been reported worldwide. We describe clinical and molecular findings of the first Brazilian patient with Keutel syndrome. Keutel syndrome was suspected based on clinical and morphological evaluation, so we sequenced the MGP gene using the TruSight One Sequencing Panel (Illumina). The obtained MGP gene sequence was then validated by Sanger sequencing. We identified a novel pathogenic homozygous variant of the MGP gene (c.2T>C; p.Met1Thr) confirming Keutel syndrome. Proper diagnosis of this syndrome is important for clinical management and is an indication for genetic counseling. Keutel syndrome should be suspected in patients with cartilage calcifications and brachydactyly when associated with a distinctive facial phenotype and pulmonary artery stenosis.

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Prostate cancer (PrCa) is among the three top most frequent and deadlier cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors having deleterious variants in homologous recombination repair (HRR) genes has placed PrCa in the roadmap of precision medicine. Still, the overall contribution of HRR genes for the 10-20% of the carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used Targeted Next Generation Sequencing (T-NGS) covering eight HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2 and RAD51C) and an analysis pipeline querying both small and large genomic variations, to clarify both their global and relative contribution for hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and then by BRCA2, RAD51C, and BRIP1 (5.6% of the carriers each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1. Additionally, 5.4% of the patients were carriers of variants of unknown significance (VUS). These results support the utility of T-NGS to clarify the genetic heterogeneity that underlies PrCa predisposition, allowing to detect both small and large genomic variations, and unveil CHEK2 and ATM as the major HRR genes associated with early-onset and familial PrCa, respectively.