YIF1B – YIF1B-related Kaya-Barakat-Masson Syndrome

Kaya–Barakat–Masson syndrome (KABAMAS) is a severe early-onset neurodevelopmental disorder characterized by profound global developmental delay, epileptic encephalopathy, microcephaly, and motor and sensory deficits. First described as a distinct entity in association with bi-allelic loss-of-function variants in YIF1B, it features progressive spasticity, dystonia, feeding difficulties, respiratory insufficiency, and visual impairment. The disorder is exceedingly rare, with only 24 patients reported to date (PMID:36948290). Affected individuals present in infancy with refractory seizures and lack of developmental milestones, often requiring supportive respiratory and nutritional interventions. Neuroimaging may show cortical and cerebellar atrophy consistent with progressive neuronal loss. The phenotype overlaps with other Golgi-related traffickinopathies, reflecting shared cellular pathways in neuronal maintenance.

Evidence supports an autosomal recessive inheritance pattern for KABAMAS. A cohort of 24 unrelated individuals from multiple families has been documented, each harboring bi-allelic predicted loss-of-function or splice-site variants in YIF1B (PMID:36948290). Segregation analysis in consanguineous pedigrees confirms co-segregation of variants with disease status, though detailed segregation counts are not specified. YIF1B encodes a membrane trafficking protein essential for endoplasmic reticulum to Golgi transport. Predicted haploinsufficiency and loss-of-function are the likely pathogenic mechanisms, consistent with recessive inheritance. No healthy homozygotes have been observed in population databases.

To date, the variant spectrum includes splice-site, nonsense, and frameshift mutations predicted to abolish YIF1B function. The recurrent homozygous splice-site variant c.297+1G>A was identified in a 5.5-year-old patient with classic KABAMAS features and is absent in homozygosity in gnomAD (VAF 0.0007%, 2 heterozygotes, 0 homozygotes) (PMID:36948290). In silico splice prediction tools uniformly predict aberrant exon skipping leading to premature truncation. This variant exemplifies the loss-of-function alleles driving the phenotype. No founder variants have been established, reflecting the rarity and diverse genetic background of affected families. Comprehensive variant databases now catalog over a dozen distinct YIF1B LoF alleles.

KABAMAS manifests with severe global developmental delay from infancy, progressing to epileptic encephalopathy with refractory seizures. Neuromotor impairment includes spasticity, dystonia, and profound hypotonia, often accompanied by feeding difficulties and early-onset respiratory failure. Visual impairment ranges from cortical blindness to ocular albinism-like features, leading to substantial sensory deficits. Other complications include dysmorphic features and failure to thrive requiring gastrostomy. Reports describe neuroimaging findings of cerebral and cerebellar atrophy consistent with neurodegeneration. Carrier frequency estimates are unavailable given the low allele frequency and disease rarity.

YIF1B encodes a four-pass transmembrane protein that facilitates anterograde trafficking from the endoplasmic reticulum to the Golgi apparatus and plasma membrane. Disruption of YIF1B in cellular models alters Golgi morphology and impairs vesicular transport, although disease-specific functional studies have not yet been reported. The predicted loss of YIF1B function likely compromises neuronal protein sorting and homeostasis, leading to neurodegeneration. Rescue of trafficking defects by wild-type YIF1B in model systems remains to be demonstrated. No patient-derived cellular assays or animal models have been described to date. Thus, functional evidence is currently limited to in silico and biochemical pathway inference.

Taken together, the consistent identification of bi-allelic YIF1B loss-of-function variants in 24 unrelated patients with a homogeneous severe neurodevelopmental phenotype establishes a strong gene-disease association. The autosomal recessive inheritance pattern, absence of healthy homozygotes in population databases, and molecular predictions of haploinsufficiency further support pathogenicity. While no direct functional studies in patient tissues are available, the convergence of genetic and cellular trafficking data implicates YIF1B haploinsufficiency as the mechanistic basis of KABAMAS. Additional studies, including patient-derived neuronal models and rescue experiments, could strengthen understanding of disease pathophysiology. Routine screening for YIF1B variants is recommended in infants presenting with severe neurodevelopmental delay, microcephaly, and early-onset epilepsy. This summary supports diagnostic decision-making and genetic counseling in clinical practice.

References

• European journal of medical genetics • 2023 • YIF1B-related Kaya-Barakat-Masson Syndrome: Report of a new patient and literature review. PMID:36948290

Evidence Based Scoring (AI generated)