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Recent evidence supports an association between biallelic variants in LNPK and a neurodevelopmental disorder characterized by epilepsy, corpus callosum hypoplasia, and developmental regression (PMID:35599435). Case reports document three independent families in which affected individuals harbor disruptive LNPK variants. This clinical report expands the phenotype by highlighting a novel frameshift mutation and accompanying neurodegenerative imaging findings, thus broadening our understanding of LNPK‑related pathology.
Detailed genetic evidence derives from case‐based studies, where affected individuals present with developmental regression in combination with epilepsy and structural brain abnormalities (PMID:35599435). In all reported families, a consistent autosomal recessive inheritance pattern is observed. The molecular analyses identified a deleterious frameshift variant that is predicted to lead to loss of normal protein function.
The identified variant, c.770del (p.Asp257fsTer31), complies with the established nomenclature guidelines. In this case, a single nucleotide deletion results in a frameshift and subsequent premature termination of translation, which supports a loss‐of‐function mechanism. Such findings are congruent with the expected molecular etiology in autosomal recessive disorders and provide critical evidence for pathogenicity.
Functional assessment studies, although preliminary, have provided supportive evidence that the LNPK mutation leads to compromised protein integrity. The experimental data hint at reduced LNPK function in cellular systems, which is consistent with the observed clinical phenotype. These studies reinforce the hypothesis that disruption of LNPK leads to neurodevelopmental abnormalities, yet further validation is warranted to fully delineate the underlying mechanisms (PMID:35599435).
The integration of genetic and functional data underscores the clinical relevance of this association. While the limited number of reported families (three, PMID:35599435) calls for cautious interpretation, the collective evidence supports a causative role for LNPK variants in this neurodevelopmental disorder. This association, therefore, provides a rational basis for incorporating genetic testing into the diagnostic workflow for patients presenting with the characteristic features.
Key take‑home sentence: Identification of the c.770del (p.Asp257fsTer31) variant in LNPK offers significant clinical utility by aiding early diagnosis and informed genetic counseling in affected families.
Gene–Disease AssociationLimitedThree unrelated families (PMID:35599435) with biallelic LNPK variants demonstrating neurodevelopmental disorder with epilepsy and corpus callosum hypoplasia support a limited gene-disease association. Genetic EvidenceModerateThe frameshift variant c.770del (p.Asp257fsTer31) identified across three independent families provides moderate genetic evidence for a loss-of-function mechanism in LNPK. Functional EvidenceLimitedPreliminary functional studies indicate that the LNPK variant compromises protein function, although further experimental validation is needed. |