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KIDINS220 encodes a 220 kDa transmembrane scaffold protein that regulates neurotrophin signaling essential for neuronal survival and differentiation. Biallelic KIDINS220 loss-of-function variants underlie the autosomal recessive form of spastic paraplegia, intellectual disability, nystagmus, and obesity (AR-SINO) syndrome, distinct from the autosomal dominant presentation caused by C-terminal truncations escaping nonsense-mediated decay. Patients typically present in infancy with lower limb spasticity, global developmental delay, feeding difficulties, ocular motor dysfunction, obesity, and seizures (HP:0001250).
Inheritance is autosomal recessive, with segregation demonstrated in a consanguineous family showing four affected fetuses (LOD 2.5) and complete co-segregation of a homozygous frameshift variant (PMID:28934391). To date, at least eight AR-SINO probands across three independent kindreds have been reported, including four fetuses, one adult cohort of four individuals, and one pediatric case with epilepsy (PMID:28934391; PMID:39033379; PMID:39296002).
Case reports include a pediatric patient with compound heterozygous KIDINS220 variants c.1556C>T (p.Thr519Met) and c.2374C>T (p.Arg792Ter) who presented with spastic paraplegia, intellectual disability, nystagmus, obesity, and epilepsy (PMID:39296002). An international cohort described four individuals harboring homozygous or compound heterozygous nonsense and frameshift variants leading to severe SINO features (PMID:39033379). Additional reports in aborted fetuses identified homozygous frameshifts disrupting the splice site in exon 24, consistent with complete loss-of-function (PMID:28934391).
The variant spectrum in AR-SINO comprises at least six loss-of-function alleles (nonsense, frameshift, splice-site) and two rare missense variants affecting conserved kinase domains. No recurrent founder alleles have been observed to date. All reported LoF variants predict premature protein truncation and activation of nonsense-mediated decay, whereas missense changes disrupt critical ankyrin and kinase‐interacting regions.
Functional studies support a haploinsufficiency mechanism: mRNA analyses confirm transcript degradation for terminal premature stop codons, and Kidins220 knockout mouse embryos exhibit hydrocephalus, enlarged cerebral ventricles, and limb contractures mirroring human fetal phenotypes (PMID:28934391). In vitro assays demonstrate absence of full-length protein and impaired Trk receptor signaling in cells expressing truncating variants.
The combined genetic and experimental data yield a strong gene–disease association. Biallelic loss-of-function in KIDINS220 produces a consistent neurodevelopmental phenotype with severe spasticity and intellectual disability. Additional heterozygous C-terminal truncations define an autosomal dominant SINO variant with milder features, highlighting the importance of variant position and NMD escape.
Key Take-home: Biallelic KIDINS220 loss-of-function variants cause autosomal recessive SINO syndrome, warranting KIDINS220 sequencing in patients with early-onset spastic paraplegia, intellectual disability, nystagmus, obesity, and seizures.
Gene–Disease AssociationStrongEight probands across three independent families with segregation (LOD 2.5) and concordant functional data Genetic EvidenceStrongSeven pathogenic alleles (five loss-of-function, two missense) in biallelic state across multiple AR-SINO families Functional EvidenceModerateMouse knockout and mRNA studies replicate human ventriculomegaly and demonstrate NMD-mediated loss-of-function |