Environmental xenobiotics such as organophosphate pesticides are known factors involved in male infertility. Paraoxanase (PON) and glutathione transferase (GST) are involved in biotransformation of organophosphate pesticides. Interindividual genetic variations in biotransformation enzyme activities can lead to differences in the susceptibility to male infertility. This case-control study investigated associations between polymorphisms in the PON and GST genes (PON1-55/192, PON2-311, GSTM1/T1) and infertility. The study group consisted of 187 infertile men (86 with non-obstructive azoospermia (NOA) and 101 with oligoasthenoteratozoospermia (OAT)), whereas the control group comprised of 194 fertile men. Statistically significant differences were found in PON1-55MM genotype (chi-squared=7.37; P=0.02) and PON1-55M allele (chi-squared=5.98; P=0.01) distribution between the infertile and fertile men. A separate analysis revealed that significant differences in genotype frequencies were limited to the OAT group (chi-squared=9.11, P=0.01). However, no significant differences in genotype frequencies of other tested polymorphisms (PON1-192, PON2-311, GSTM1/T1) and male infertility were observed. The PON1-55M allele might represent a risk factor for infertility susceptibility in Slovenian men. Further studies with a larger sample size are needed to confirm these findings.

BackgroundOur aim was to conduct a comprehensive genetic evaluation using the combination of QF‐PCR (quantitative fluorescence polymerase chain reaction) and aCGH (array comparative genomic hybridization) for the detection of the frequency and type of chromosome aberrations in recurrent miscarriage (RM) in the clinical setting.MethodsThis retrospective study was conducted on 73 first‐trimester products of conception (POC) between September 2014 and February 2017. The POCs were collected from 73 women with at least one previous miscarriage and analyzed for chromosomal anomalies using QF‐PCR and aCGH as part of the routine clinical evaluation.ResultsChromosome aberrations were detected in 52/73 POCs (71.2%), of which 41 (56.2%) were identified by QF‐PCR and an additional 11 (15.1%) by aCGH. Numerical aberrations constituted 92.3% of abnormalities, with trisomies as the most common subtype (72.9%). Causative structural aberrations were found in three samples (5.8%). The frequency of chromosome aberrations was not dependent on the number of previous miscarriages, whereas it significantly increased with advanced maternal age.ConclusionOur results confirm that chromosome aberrations are the most common cause of RM and that QF‐PCR and aCGH combination should be included in the routine genetic analysis of POCs of couples with miscarriage.

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Background and ObjectivesTo report on the novel association of biallelic variant in atonal basic helix-loop-helix transcription factor 1 (ATOH1) gene and pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss in a family with 2 affected siblings.MethodsA detailed clinical assessment and exome sequencing of peripheral blood sample were performed. Segregation analysis with Sanger sequencing and structural modeling of the variant was performed to support the pathogenicity of the variant.ResultsA homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister. The segregation analysis subsequently confirmed its segregation with an apparently recessive PCH in this family. ATOH1 encodes for the atonal basic helix-loop-helix (bHLH) transcription factor 1, a core transcription factor in the developing cerebellum, brainstem, and dorsal spinal cord, and in the ear. The identified variant results in the p.(Arg161Gly) amino acid substitution in the evolutionarily conserved DNA-binding bHLH domain of the ATOH1 protein. Biallelic missense variants in this domain were previously reported to result in disordered cerebellar development and hearing loss in animal models. In silico homology modeling revealed that p.Arg161Gly in ATOH1 protein probably disrupts a salt bridge with DNA backbone phosphate and increases the flexibility of the bHLH helix–both of which together affect the binding capability of the bHLH domain to the DNA.DiscussionBased on the sequencing results and evidence from structural modeling of the identified variant, as well as with previous reports of ATOH1 gene disruption, we conclude that ATOH1 may represent a novel candidate gene associated with the phenotype of PCH, global developmental delay, and hearing loss in humans.