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SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel's function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants' characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions. [ABSTRACT FROM AUTHOR]

Shwachman Diamond Syndrome (SDS) is a multi-system disease characterized by exocrine pancreatic insufficiency with malabsorption, infantile neutropenia and aplastic anemia. Life-threatening complications include progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), critical deep-tissue infections and asphyxiating thoracic dystrophy. In most patients, SDS results from biallelic pathogenic variants in the SBDS gene, different combinations of which contribute to heterogenous clinical presentations. Null variants are not well tolerated, supporting the theory that the loss of SBDS expression is likely lethal in both mice and humans. A novel complex genotype (SBDS:c.[242C>G;258+2T>C];[460-1G>A]/WFS1:c.[2327A>T];[1371G>T]) was detected in a family with recurrent neonatal deaths. A female neonate died three hours after birth with hemolytic anemia, and a male neonate with severe anemia, thrombocytopenia and neutropenia succumbed on day 40 after Staphylococcus epidermidis infection. A subsequent review of the literature focused on fatal complications, complex SBDS genotypes and/or unusual clinical presentations and disclosed rare cases, of which some had unexpected combinations of genetic and clinical findings. The impact of pathogenic variants and associated phenotypes is discussed in the context of data sharing towards expanding scientific expert networks, consolidating knowledge and advancing an understanding of novel underlying genotypes and complex phenotypes, facilitating informed clinical decisions and disease management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diamond–Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated. [ABSTRACT FROM AUTHOR]

Whole-Exome Sequencing (WES) has proven valuable in the characterization of underlying genetic defects in most rare diseases (RDs). Copy Number Variants (CNVs) were initially thought to escape detection. Recent technological advances enabled CNV calling from WES data with the use of accurate and highly sensitive bioinformatic tools. Amongst 920 patients referred for WES, 454 unresolved cases were further analysed using the ExomeDepth algorithm. CNVs were called, evaluated and categorized according to ACMG/ClinGen recommendations. Causative CNVs were identified in 40 patients, increasing the diagnostic yield of WES from 50.7% (466/920) to 55% (506/920). Twenty-two CNVs were available for validation and were all confirmed; of these, five were novel. Implementation of the ExomeDepth tool promoted effective identification of phenotype-relevant and/or novel CNVs. Among the advantages of calling CNVs from WES data, characterization of complex genotypes comprising both CNVs and SNVs minimizes cost and time to final diagnosis, while allowing differentiation between true or false homozygosity, as well as compound heterozygosity of variants in AR genes. The use of a specific algorithm for calling CNVs from WES data enables ancillary detection of different types of causative genetic variants, making WES a critical first-tier diagnostic test for patients with RDs. [ABSTRACT FROM AUTHOR]