| Evidence domain | DFNB26 finding | Evidence status | Source |
|---|---|---|---|
| Disease/locus | Autosomal recessive nonsyndromic hearing loss 26 (**DFNB26**), originally linked in Pakistani family PK-2 to a 1.5-cM interval at chromosome **4q31** | Demonstrated by human linkage and segregation | (pqac-00000001, pqac-00000004) |
| Causal variant | Homozygous **GAB1** transcript NM_207123 **c.347G>A, p.(Gly116Glu)**; affects a conserved residue in the pleckstrin-homology domain and was absent from the examined controls and 1000 Genomes, NHLBI-ESP, and ExAC | Demonstrated in one extended pedigree; functional evidence supports a hypomorphic allele | (pqac-00000003, pqac-00000004) |
| Phenotype | Prelingual, bilateral, severe-to-profound/profound sensorineural hearing loss without reported extra-auditory manifestations | Demonstrated clinically in PK-2; exact thresholds, ages, progression, and individual-level audiograms were not reported in the extracted evidence | (pqac-00000003, pqac-00000007) |
| Genetic modifier | A dominant modifier at **DFNM1**, **METTL13 c.1631G>A, p.(Arg544Gln)**, was carried by normal-hearing individuals homozygous for GAB1 p.Gly116Glu; affected homozygotes lacked the modifier | Demonstrated by pedigree segregation; suppression supported experimentally. One extracted passage reports c.1634G>A, but the primary-study sequence-level result is c.1631G>A, so transcript-version verification is advisable | (pqac-00000001, pqac-00000003, pqac-00000004) |
| Molecular mechanism | GAB1 functions as an adaptor in **HGF–MET** signaling. p.Gly116Glu impairs PH-domain lipid-related function; affected lymphoblastoid cells showed selective **SPRY2** upregulation, and GAB1, METTL13, and SPRY2 formed a supported tripartite complex | GAB1 dysfunction and signaling dysregulation are experimentally supported; the complete cochlear chain from variant to hair-cell dysfunction is inferred rather than demonstrated | (pqac-00000002, pqac-00000005, pqac-00000010) |
| Evidence systems | Human linkage, exome sequencing, segregation, and lymphoblastoid-cell expression; biochemical lipid-binding and co-immunoprecipitation assays; COS-7 interaction assays; zebrafish morpholino/mRNA rescue; mouse inner-ear expression and colocalization; later mouse cochlear single-cell transcriptomic context | Mixed human, in vitro, zebrafish, mouse-localization, and transcriptomic evidence; no reported mammalian GAB1 p.Gly116Glu knock-in model | (pqac-00000001, pqac-00000002, pqac-00000005, pqac-00000012) |
| Major data gaps | No replicated unrelated DFNB26 families, disease-specific prevalence/incidence, quantitative penetrance, carrier frequency, longitudinal natural history, validated prognostic biomarkers, DFNB26-specific therapy/trial, or definitive disease-specific mammalian model identified | Unavailable; mechanism, penetrance, and genotype–phenotype estimates remain constrained by a single pedigree | (pqac-00000001, pqac-00000003, pqac-00000007) |


*Table: Compact summary of the human genetic, modifier, mechanistic, and model-system evidence for GAB1-related DFNB26. It distinguishes demonstrated findings from pathway-level inference and highlights the major knowledge gaps.*