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Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive neuromuscular disorder marked by ataxia, muscle weakness, cataracts, and often intellectual and skeletal abnormalities. It is commonly caused by loss-of-function variants in the SIL1 gene, which impair binding immunoglobulin protein (BiP) function, leading to protein misfolding and activation of the unfolded protein response. In a 2-year-old patient with typical MSS symptoms, we identified a previously unreported c.1024G>A (p.E342K) variant in SIL1 via whole-exome sequencing. The pathogenicity of this Sil1 variant was supported by evidence of structural changes revealed through in silico predictions, circular dichroism, and native gel electrophoresis. Patient-derived fibroblasts exhibited reduced Sil1 protein levels, likely due to misfolding and degradation, which was partially rescued by proteasome inhibition. Proteomics revealed a profile similar to known MSS cases and a distinctive MSS transcriptional signature. Ultrastructural analysis confirmed typical MSS features, such as autophagic vacuoles and lipid droplets. Although the p.E342K phenotype appears milder than the reference pathogenic variant R111X, our findings support the reclassification of this novel variant as pathogenic, in accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines and the refinements proposed by the Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations. Furthermore, the overall evidence also provides important insights into the genotype–phenotype correlation and the underlying pathogenic mechanism of the p.E342K variant.

The development of high-throughput technologies has enabled Expanded Carrier screening (ECS) as a more comprehensive and extensive approach for high‐risk populations. The available methods of ECS are population-targeted gene-panels according to ethnicity, however these panels should be planned according to a real-world data evaluation. In this study, we estimate the frequency of pathogenic variants for autosomal-recessive and X-linked conditions in Exome Sequencing-ES data for a 176 gene panel proposed from ACMG and ACOG in a Greek cohort. ES data from 1000 unrelated individuals was evaluated for pathogenic SNVs and CNVs. Variants were filtered using 5% Minor Frequency Allele (MAF), ClinVar submissions, and classification with ACMG criteria. For the at-risk couple rate, we hypothesized that both parents carried variants in the same gene. It is noted that many common conditions (hemoglobinopathies, SMA, Fragile-X) may escape NGS-based detection as they require alternative methods for optimal detection. Amongst 1000 participants, 32% were heterozygous for at least one disorder and 14% for two or more, whereby 393 unique pathogenic/likely pathogenic heterozygous variants were identified. We calculated that 1.6% of couples have a risk for at least one AR condition, which means that for 85,000 births per year, 1380 couples require genetic counseling. This study provides data confirming that the ACMG/ACOG ECS list of 176 genes is suitable for carrier screening in Greece, and aids counseling prospective parents for residual risk, however it should be supported by appropriate interpretation and reproductive options, as well as ancillary genetic testing methods.

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A ) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A>T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient’s favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype–phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies.

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A>T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient’s favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype–phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies.