A total of 84 patients (71 families) with a clinical diagnosis of inherited deaf-blindness were included. Most patients were males (58.3%, n = 49), and the mean age at molecular diagnosis was 40.0 ± 17.9 years (range 5–74 years). Family history of the disease was present in 43.7% of our cohort (n = 31 families), while 38.0% (n = 27) of families reported consanguinity. All patients were followed for a median period of 80 months (interquartile range 12–110 months). The demographic characterization of the cohort is presented in Table 1, while the cohort distribution per district of residence is presented in Fig. 1.

Cohort distribution by district of residence (data presented per patient)

USH was the most frequent etiology (71.4%, n = 60 patients, 52 families) followed by PHARC syndrome (6.0%, n = 5, 3 families), Autosomal dominant optic atrophy plus (ADOA plus) (4.8%, n = 4, 2 families) and cone-rod dystrophy and hearing loss (4.8%, n = 4, 4 families). Other less frequent etiologies included Alport syndrome (3.6%, n = 3, 3 families), Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (2.4%, n = 2, 2 families), Heimler syndrome (2.4%, n = 2, 1 family), Senior-Loken syndrome (1.2%, n = 1, 1 family), Waardenburg syndrome (1.2%, n = 1, 1 family), MIDD (1.2%, n = 1, 1 family), and Stickler syndrome (1.2%, n = 1, 1 family) (Fig. 2). Regarding Usher syndrome, type II was the most frequently encountered (51.7%, n = 31 patients, 25 families), followed by type I (28.3%, n = 17 patients, 16 families) and type IV (8.3%, n = 5 patients, 4 families). Seven patients (7 families) with a clinical diagnosis of USH remained genetically unsolved.

Cohort diagnosis distribution (percentage per patient). ADOA plus—Autosomal dominant optic atrophy plus; MELAS—Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episode; PHARC—Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataract syndrome; MIDD—Maternally inherited diabetes and deafness

The reported visual acuity ranged from 20/20 Snellen equivalent to no light perception. The mean baseline BCVA for this cohort was 58.8 ETDRS letters (Snellen equivalent ~ 20/63), declining to 50.5 ETDRS letters (Snellen equivalent ~ 20/100) at the last follow-up (median 80 months; IQR 12–110 months) (p < 0.001).

Age of ophthalmic disease onset, defined as the first instance of ophthalmic-attributable symptoms is presented in Table 1, with most patients reporting the beginning of visual symptoms before 30 years of age. The most frequently observed phenotypes were rod-cone dystrophy (80.95%, n = 68 patients), cone-rod dystrophy (4.76%, n = 4 patients), macular dystrophy (7.14%, n = 6 patients), and optic neuropathy (4.76%, n = 4 patients).

The majority of patients (60.7%, n = 51) reported HL before adult age, while thirty-four patients (40.1%) presented with prelingual HL. Most patients (74.6%, n = 50) had an electronic hearing device, with 19.1% (n = 16) of these having cochlear implants.

All patients with Usher type 1 and Heimler syndrome presented with prelingual HL, while Usher type 4, PHARC, and MELAS manifested HL during adulthood. The hearing impairment by age of symptoms and diagnosis are presented in Table 2.

Fifty patients (59.5%) were referred to genetic counseling and molecular diagnosis after consultation with an Ophthalmologist. Otorhinolaryngology accounted for 16.7% (n = 14) of genetic referrals, while other specialties such as Pediatrics, Nephrology, Neurology, and Endocrinology contributed to the remaining referrals.

Disease-causing variants were identified in 52/71 families, resulting in an overall diagnostic yield of 73.2%. Further details on the diagnostic yield and all involved genes per diagnosis are provided in Table 3. A total of 55 unique variants were identified across 16 genes. Eleven variants are novel and herein reported for the first time. These were found in USH2A, MYO7A, CEP250, ARSG, COL4A5, CDH23, OPA1, LPL/SDCCAG8, and COL11A1 genes. A detailed description of all identified genetic variants is presented in Table 4.

Among solved cases of combined IRD and HL, different patterns of inheritance were verified. Most families (n = 50, 70.4%) exhibited autosomal recessive (AR), followed by autosomal dominant (AD) in 5.6% of families (n = 4), X-linked in 1 family (1.4%) and mitochondrial DNA-dependent syndromes in three families (4.2%). Among cases with AR inheritance, a single disease-causing variant in homozygosity was identified in 31 families (62.0%), while 12 (24.0%) presented two different variants in compound heterozygosity. A detailed description of the zygosity of all genetic variants across all the families is presented in Table 5.

Among the unsolved cases (19 families), 12 families were subclassified as partially solved: 9 families (12.7%) presented with a VUS, while 3 families (4.3%) harbored one pathogenic/likely pathogenic variant and a VUS in genes associated with the phenotype. The majority were in recessively inherited genes (n = 4 in USH2A, n = 2 in ARSG, n = 2 in MYO7A, n = 1 in ADGRV1, and n = 1 in ABHD12), and two in OPA1 gene.