Abdelhamid Bouramtane

Background: Parental imprinting plays a crucial role in epigenetic regulation and is increasingly recognized for its involvement in neurodevelopmental disorders. Although ATP8A2 is considered a non-imprinted gene; However, the marked phenotypic variability observed across related disorders suggests that additional regulatory layers may influence its expression. Methods: We investigated the imprinting-like status of ATP8A2 through functional analyses of a splicing variant (c.1580-3C>G) identified in a patient diagnosed with Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome type 4 (CAMRQ4). Sanger sequencing was used to assess allelic expression and identify aberrant transcripts. Results: Our analyses revealed an allelic expression imbalance suggestive of parental imprinting of ATP8A2. Moreover, Sanger sequencing led to the identification of a novel ATP8A2–RAB3GAP2 chimeric transcript, pointing to a previously unreported transcriptional event, the functional relevance of which remains to be determined. Conclusions: These findings indicate that ATP8A2 may be subject to imprinting-like regulation and involved in atypical splicing events with unknown significance. This highlights the need for further investigation into the epigenetic and transcriptional complexity of ATP8A2-related neurodevelopmental disorders.

Familial cold autoinflammatory syndrome 2 is a rare autoinflammatory disorder caused by mutations in the NLRP12 gene, characterized by recurrent fever, arthralgia and rash triggered by cold exposure. This case report presents a 9‐year‐old boy with intellectual disability, microcephaly and skin lesions, where genetic testing revealed heterozygous pathogenic variants in both KIF11 (NM_004523.4:c.2304_2305del) and NLRP12 (NM_144687.4:c.770del) genes. While the KIF11 variant has been previously documented, the NLRP12 variant is novel and classified as likely pathogenic. This study also includes a systematic review analysing 28 studies and 100 patients with NLRP12 mutations, revealing a phenotypic spectrum ranging from classic symptoms like fever and rash to rarer features such as hypogonadism, hypothyroidism and neurological abnormalities. A significant concentration of variants was noted in Exon 3 of NLRP12 , but no clear genotype–phenotype correlation was established. These findings underscore the utility of next‐generation sequencing in diagnosing rare genetic conditions, particularly in patients presenting with seemingly minor symptoms. The coexistence of mutations in KIF11 and NLRP12 highlights potential interactions between distinct genetic pathways, emphasizing the need for further research. Including NLRP12 in diagnostic panels and updating databases like the Human Phenotype Ontology are crucial for improving diagnosis, understanding phenotypic diversity and optimizing patient management.

Background Cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4 (CAMRQ4) is a rare autosomal recessive neurological disorder caused by biallelic variants in the ATP8A2 gene. It is characterized by severe psychomotor impairment, hypotonia or spasticity, and intellectual disability. Despite increasing case reports, the full phenotypic spectrum remain incompletely defined. Methods We report the case of a 7-year-old girl born to consanguineous parents, presenting with severe psychomotor delay, quadriplegia, and craniofacial dysmorphisms. Whole exome sequencing identified a novel splicing variant in ATP8A2 (NM_016529.6:c.1580-3C > G). In silico tools predicted a disruption of the canonical splice acceptor site. To confirm the splicing effect, RNA was extracted from peripheral blood, followed by cDNA synthesis and PCR amplification of the region flanking the variant. Products were analyzed via gel electrophoresis. Results Experimental validation revealed skipping of exon 18, confirming a significant impact on splicing and supporting the reclassification of the variant as “likely pathogenic” based on ACMG criteria (PM2, PP3, and now PS3). Additionally, a systematic literature review of published CAMRQ4 cases was conducted to delineate the clinical heterogeneity associated with ATP8A2 variants. Conclusions This case expands the mutational spectrum of ATP8A2 and provides strong evidence for the pathogenicity of a novel splicing variant. Our findings emphasize the clinical and genetic heterogeneity of CAMRQ4 and highlight the critical role of functional RNA studies in variant interpretation. Comprehensive genotype–phenotype correlation through systematic review enhances our understanding of ATP8A2-related disorders.