NBAS – SOPH Syndrome

Neuroblastoma-amplified sequence (NBAS; HGNC:15625) biallelic variants underlie an autosomal recessive multisystem disorder primarily characterized by short stature, optic atrophy, and Pelger-Huët anomaly, collectively termed SOPH syndrome (MONDO:0013889). While originally described in Yakut individuals homozygous for the founder c.5741G>A (p.Arg1914His) variant without liver involvement, subsequent reports have expanded the phenotype to include fever-triggered recurrent acute liver failure in compound heterozygotes (28031453).

Genetic evidence for NBAS–SOPH association includes at least 7 probands from 4 unrelated families with confirmed biallelic NBAS variants demonstrating classic shortening of stature, optic nerve degeneration, and granulocyte nuclear anomalies (28031453)(30622725)(36479642)(31015584). Variants span missense (including founder p.Arg1914His), nonsense, frameshift, and splice-site changes. Segregation analysis in two affected sisters and parental carrier status further supports pathogenicity (36479642).

Functional studies in patient fibroblasts reveal that NBAS deficiency disrupts Golgi-to–endoplasmic reticulum retrograde trafficking, with temperature-sensitive protein instability and impaired syntaxin 18 complex tethering, explaining fever-dependent liver crises and multisystem involvement (26541327). Rescue of liver episodes by early antipyretic and anabolic therapy underscores therapeutic implications.

Phenotypic variability is notable: some NBAS alleles (e.g., p.Arg1914His homozygotes) manifest isolated short stature and optic atrophy without liver failure, whereas compound heterozygotes may present with recurrent acute liver failure (30622725). Additional manifestations include skeletal dysplasia, immunodeficiency, cone dystrophy, and osteogenesis imperfecta in select patients, reflecting domain-specific genotype–phenotype correlations (31761904).

No significant conflicting evidence has emerged to refute the NBAS–SOPH link, though deep intronic and hypomorphic variants require functional validation to establish pathogenicity definitively (36479642). Population data remain limited but founder effects are evident in distinct ethnic groups.

In summary, NBAS biallelic variants cause a clinically recognizable, autosomal recessive SOPH syndrome with occasional liver crisis, supported by robust genetic and experimental data. Early genetic testing and tailored management, including antipyresis, can improve outcomes. Key take-home: NBAS analysis is essential for children presenting with short stature, optic atrophy, Pelger-Huët anomaly, and intermittent liver dysfunction.

References

• Pediatrics • 2017 • Acute Liver Failure Meets SOPH Syndrome: A Case Report on an Intermediate Phenotype. PMID:28031453
• Human genome variation • 2019 • Novel neuroblastoma amplified sequence (NBAS) mutations in a Japanese boy with fever-triggered recurrent acute liver failure. PMID:30622725
• Molecular genetics & genomic medicine • 2023 • Characterization of a novel non-canonical splice site variant (c.886-5T>A) in NBAS and description of the associated phenotype. PMID:36479642
• Journal of human genetics • 2019 • SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy. PMID:31015584
• Journal of inherited metabolic disease • 2016 • Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts. PMID:26541327
• Genetics in medicine : official journal of the American College of Medical Genetics • 2020 • Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients. PMID:31761904

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