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Elongation Factor-Like 1 (EFL1) is a GTPase that cooperates with the Shwachman-Bodian-Diamond syndrome protein (SBDS) to evict eIF6 from the 60S ribosomal subunit, a critical step in 80S ribosome maturation. Pathogenic biallelic variants in EFL1 have been identified in patients presenting with bone marrow failure, exocrine pancreatic insufficiency and skeletal anomalies characteristic of Shwachman-Diamond syndrome (SDS). Although SBDS mutations account for ~90% of SDS, EFL1 deficiency defines a genetically distinct autosomal recessive ribosomopathy overlapping the SDS phenotype.
Genetic evidence includes 14 unrelated probands with biallelic EFL1 variants across six studies, including 6 patients from three consanguineous families homozygous for c.3284G>A (p.Arg1095Gln) and c.2645T>A (p.Met882Lys) ([PMID:28331068]), 3 unrelated individuals harboring five distinct variants including c.2909G>A (p.Arg970His) and c.2260C>T (p.Arg754Ter) ([PMID:31151987]), and additional singleton cases with c.379A>G (p.Thr127Ala) ([PMID:29970384]) and compound heterozygous c.89A>G (p.His30Arg) plus c.2599A>G (p.Asn867Asp) ([PMID:39379149]). The variant spectrum comprises missense substitutions and protein-truncating alleles affecting conserved domains, without evidence of a founder effect. Inheritance is autosomal recessive, with pathogenic variants segregating in multiple pedigrees and no unaffected homozygotes reported.
Functional studies in yeast and human cells demonstrate that EFL1 mutants fail to promote eIF6 release, leading to cytoplasmic Tif6/eIF6 accumulation and impaired 80S assembly. Yeast complementation assays show relocalization of Tif6-GFP to the cytoplasm in p.Arg1095Gln and p.Met882Lys mutants ([PMID:28331068]). Patient-derived lymphoblastoid and fibroblast lines with p.His30Arg/p.Asn867Asp variants exhibit defective ribosomal subunit joining and attenuated global translation ([PMID:39379149]). Mouse models of Efl1 deficiency recapitulate key hematopoietic and pancreatic features of SDS ([PMID:31151987]).
Somatic uniparental disomy in three Korean patients carrying biallelic EFL1 variants (p.Thr1069Ala, p.Gly827fs, p.His30Arg) highlights allele-specific effects and the capacity of milder variants to cause SDS features despite mosaic rescue ([PMID:34115847]). Molecular dynamics and SAXS studies further support an allosteric mechanism of EFL1 dysfunction, with domain IV hinge movements disrupted in p.Thr127Ala and p.Arg1095Gln mutants ([PMID:31838967]).
Collectively, the genetic and experimental data fulfill ClinGen criteria for a "Strong" gene-disease association based on >10 probands, multi-family segregation and concordant functional models. EFL1 should be included in diagnostic gene panels for SDS and related ribosomopathies, as early molecular diagnosis informs hematologic monitoring and potential ribosome-targeted therapies.
Key Take-home: Autosomal recessive EFL1 variants cause a clinically and mechanistically defined ribosomopathy overlapping Shwachman-Diamond syndrome, warranting incorporation into diagnostic workflows.
Gene–Disease AssociationStrong14 unrelated probands with biallelic EFL1 variants, multi-family segregation, concordant functional data Genetic EvidenceStrongBiallelic missense and truncating variants in 14 probands across six studies; AR inheritance Functional EvidenceModerateYeast and mammalian cell assays and mouse models demonstrate impaired eIF6 release and 80S assembly |