Novel Variants Identified in Families With <scp> <i>SNX27</i> </scp> ‐Related Neurodevelopmental Disorder, Aiding in Characterizing Its Genotypic and Phenotypic Spectrum

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype. Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome or genome sequencing. This revealed a novel homozygous frameshift variant in family I [NM_001330723.2: c.75dup; p. (Ser26Valfs*85)], predicted to be targeted by nonsense-mediated decay. In family II, a novel homozygous missense variant [NM_001330723.2: c.929 T>C; p. (Met310Thr)] was found within the FERM-like region of the SNX27 protein, which is critical for retromer complex interaction. Comparison of five cases described in this study with previously reported six cases reinforces the presence of consistent "core" clinical features-global developmental delay, intellectual disability, speech delay, behavioral abnormalities, seizures, and motor dysfunction in all assessed cases. Other features such as dental anomalies, failure to thrive, and dysmorphisms occurred variably in few. Affected individuals with predicted loss-of-function variants typically presented with a more severe phenotype. Thus, core features of SNX27-related neurodevelopmental disorders (NDDs) are intellectual disability, developmental, and speech delays. This study, alongside prior reports, augments the genetic and phenotypic spectrum of SNX27-associated NDDs. The novel frameshift variant p.(Ser26Valfs*85) is predicted to severely disrupt SNX27 function, causing profound neurodevelopmental impairment, whereas the missense p.(Met310Thr) in the FERM-like region is associated with a milder phenotype. Comparative analyses with previous reports reveal a spectrum from early lethality to long-term survival with intellectual disability in SNX27-linked families. These findings underscore the importance of SNX27 in neurodevelopment and further validate its link to a neurodevelopmental disorder.