A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.

Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called "mild" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.

Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America.

Achromatopsia (ACHM) is a severe retinal disorder characterized by an inability to distinguish colors, impaired visual acuity, photophobia and nystagmus. This rare autosomal recessive disorder of the cone photoreceptors is best known for its increased frequency due to founder effect in the Pingelapese population of the Pacific islands. Sixteen patients from Newfoundland, Canada were sequenced for mutations in the four known achromatopsia genes CNGA3, CNGB3, GNAT2, and PDE6C. The majority (n = 12) of patients were either homozygotes or compound heterozygotes for known achromatopsia alleles, two in CNGB3 (p.T383fsX and p.T296YfsX9) and three in CNGA3 (p.R283Q, p.R427C and p.L527R). Haplotype reconstruction showed that recurrent mutations p.T383fsX and p.L527R were due to a founder effect. Aggregate data from exome sequencing, segregation analysis and archived medical records support a rediagnosis of Jalili syndrome in affected siblings (n = 4) from Family 0094, which to our knowledge is the first family identified with Jalili Syndrome in North America.

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype-phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.