NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations

Abstract

The pathogenic variants in the neuroblastoma‐amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole‐exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co‐occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and “progeroid” appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype–phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS‐Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N‐terminus and C‐terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss‐of‐function.

Complex Multisystem Phenotype With Immunodeficiency Associated With NBAS Mutations: Reports of Three Patients and Review of the Literature

“…Progressive reduction in NK cells numbers has been described by Garcia Segarra et al (15) and then by Ricci et al (10). As Figure 2 demonstrates, the patients who had immunodeficiency and bone disease had mutations distributed along the gene, with no particular domain predominance (10,(14)(15)(16)(17)(18)(19)(20)(21)(22)(27)(28)(29)(30)(31)(32)(33)(34)(35), current study).…”

“…This syndrome is characterized by autosomal recessive inheritance, severe postnatal growth impairment, facial dysmorphisms with senile face, small hands and feet, and normal intelligence. Subsequent case reports have described immunological defects in some patients with SOPH syndrome (10,(15)(16)(17)(18)(19)(20)(21)(22). Recent studies demonstrated SOPH syndrome to be only a part of a clinical spectrum ranging from isolated acute liver failure to a complicated phenotype that includes skeletal dysplasia, immunological abnormalities, and the involvement of other organs (10,16).…”

Genetic similarity and facial cues for kin recognition in humans

“…Genetic studies of chromosomal anomalies have found predictable relationships between facial traits, such as nasal bridge and eyebrow shape or dental features, and microdeletions or translocations [9,24] Facial similarity and perception of selfresemblance in the present study is likely unrelated to genetic and chromosomal abnormalities. Therefore, the feasibility of finding a positive relationship between genes and facial features is supported by previous studies of phenotype and chromosomal anomalies.…”

Infantile fever-triggered acute liver failure caused by novel neuroblastoma amplified sequence mutations: a case report

“…NBAS mutations have also been identified in SOPH syndrome patients without liver failure [4]. An increasing number of studies have indicated that diseases based on NBAS mutations have a broad phenotypic spectrum, ranging from isolated recurrent ILFS2 to a multi-systemic disease manifesting as short stature, skeletal dysplasia, dysmorphism and optic atrophy with or without liver failure [4][5][6][7][8][9][11][12][13][14][15][16][17][18].…”