Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia.

Microphthalmia is an important developmental eye disorder. Although mutations in several genes have been linked to this condition, they only account for a minority of cases. We performed autozygome analysis and exome sequencing on a multiplex consanguineous family in which colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities, and we identified a homozygous truncating mutation in C12orf57 [c.1A>G; p.Met1?]. In a simplex case with a similar phenotype, we identified compound heterozygosity for the same mutation and another missense mutation [c.152T>A; p.Leu51Gln]. Little is known about C12orf57 but we show that it is expressed in several mouse tissues, including the eye and brain. Our data strongly implicate mutations in C12orf57 in the pathogenesis of a clinically distinct autosomal-recessive syndromic form of colobomatous microphthalmia.

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes.

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies.

PURPOSE: Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. METHODS: We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. RESULTS: Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. CONCLUSION: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med 18 6, 554-562.

The application of artificial intelligence in diabetic retinopathy screening: a Saudi Arabian perspective.

Introduction: Diabetic retinopathy (DR) is the leading cause of preventable blindness in Saudi Arabia. With a prevalence of up to 40% of patients with diabetes, DR constitutes a significant public health burden on the country. Saudi Arabia has not yet established a national screening program for DR. Mounting evidence shows that Artificial intelligence (AI)-based DR screening programs are slowly becoming superior to traditional screening, with the COVID-19 pandemic accelerating research into this topic as well as changing the outlook of the public toward it. The main objective of this study is to evaluate the perception and acceptance of AI in DR screening among eye care professionals in Saudi Arabia. Methods: A cross-sectional study using a self-administered online-based questionnaire was distributed by email through the registry of the Saudi Commission For Health Specialties (SCFHS). 309 ophthalmologists and physicians involved in diabetic eye care in Saudi Arabia participated in the study. Data analysis was done by SPSS, and a value of p < 0.05 was considered significant for statistical purposes. Results: 54% of participants rated their level of AI knowledge as above average and 63% believed that AI and telemedicine are interchangeable. 66% believed that AI would decrease the workforce of physicians. 79% expected clinical efficiency to increase with AI. Around 50% of participants expected AI to be implemented in the next 5 years. Discussion: Most participants reported good knowledge about AI. Physicians with more clinical experience and those who used e-health apps in clinical practice regarded their AI knowledge as higher than their peers. Perceived knowledge was strongly related to acceptance of the benefits of AI-based DR screening. In general, there was a positive attitude toward AI-based DR screening. However, concerns related to the labor market and data confidentiality were evident. There should be further education and awareness about the topic.

Effect of Pegylated Interferon and Mitomycin C on Ocular Surface Squamous Neoplasia in Xeroderma Pigmentosum: A Case Series.

BACKGROUND Xeroderma pigmentosum (XP) is an autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations include extreme sensitivity to ultraviolet (UV) rays, freckle-like pigmentation, ocular abnormalities, and an increased risk of developing neoplasms in sun-exposed areas of the skin, mucous membranes, and eyes. This paper describes the clinical outcome of pegylated interferon alpha 2b (PEG-IFN-alpha-2b) subconjunctival injections and topical mitomycin C (MMC) in the treatment of ocular surface squamous neoplasia (OSSN) in patients with XP. CASE REPORT A series of 3 patients with histopathologically-proven biopsy specimens of XP-associated neoplasia of the eyelids and ocular surface underwent subconjunctival injections of PEG-IFN-alpha-2 band topical cycles of MMC. There was a noticeable decrease in the size and severity of ocular surface squamous neoplasia, with minimal adverse effects of flu-like symptoms with mild fever and generalized malaise. Transient mental depression was reported in 2 of our patients, and only 1 patient developed autoimmune diabetes mellitus, which required insulin therapy after the discontinuation of the PEG-IFN-alpha-2b. CONCLUSIONS The literature on the specifics of ocular care using PEG-IFN-alpha-2b for XP-associated OSSN is sparse. However, according to our clinical experience, the combination of PEG-IFN-alpha-2b subconjunctival injection and the topical cycles of MMC is a promising long-term medical therapy to minimize the development and recurrence of OSSN in XP patients.

Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss.

Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study's objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in "Ca2+" ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.

Unusual Association of Aniridia with Aicardi-Goutières Syndrome-Related Congenital Glaucoma in a Tertiary Care Center.

BACKGROUND Aicardi-Goutières syndrome (AGS) is a rare autosomal recessive encephalopathy of early onset. AGS visual dysfunction range from nystagmus and optic atrophy to cortical blindness in affected individuals; however, congenital glaucoma has been recently noticed among AGS pediatric patients. According to the literature, aniridia has never been recognized among AGS patients. CASE REPORT We report the case of a 4-year-old boy with AGS who had multiple congenital anomalies in the eyes. He was found to have congenital glaucoma, nystagmus, spherophakia with shallow chambers, and aniridia in both eyes. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents are carriers of congenital glaucoma genes. A whole-exome sequencing identified IFIH1 heterozygous missense mutation of the patient, which is associated with AGS Type 7. Also, he was diagnosed as having congenital glaucoma with CYP1B1 mutation, homozygous recessive. This case demonstrates the unusual coexistence of bilateral aniridia, a feature not previously reported in ocular findings of AGS. CONCLUSIONS In summary, this is the first reported case of aniridia with AGS-related congenital glaucoma in the literature. This paper summarizes the usual ocular manifestation of AGS, also it highlights atypical ocular features in both; AGS as well as congenital glaucoma. The aim of this paper is to lay the foundation for a national database on AGS in Saudi Arabia, which will help create a bridge between genetic data and clinical findings of AGS patients.

Utility of whole exome sequencing in the diagnosis of Usher syndrome: Report of novel compound heterozygous MYO7A mutations.

Next generation sequencing (NGS), such as targeted panel sequencing, whole-exome sequencing and whole-genome sequencing has led to an exponential increase of elucidated genetic causes in both rare diseases, and common but heterogeneous disorders. NGS is applied in both research and clinical settings, and the clinical exome sequencing (CES), which provides not only the sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to a genetic diagnosis. Usher syndrome is a group of disorders, characterized by bilateral sensorineural hearing loss, with or without vestibular dysfunction and retinitis pigmentosa. The index patient, a 2-year-old child was initially diagnosed with nonsyndromic hearing impairment. Homozygosity mapping followed by CES was utilized as a diagnostic tool to identify the genetic basis of his hearing loss. A paternally inherited novel insertion, c.198_199insA (p.Val67Serfs*73) and a maternally inherited novel deletion, c.1219_1226del (p.Phe407Aspfs*33) in gene MYO7A were found in compound heterozygous state in the index patient. The result expands the mutational spectrum of MYO7A. In addition it helped in early diagnosis of the syndrome, for planning and adjustments for the patient, and as well as for future family planning. This study highlights the clinical effectiveness of CES for Usher syndrome diagnosis in a child presented with congenital hearing loss.

COL4A4-related nephropathy caused by a novel mutation in a large consanguineous Saudi family.

INTRODUCTION: Collagen type IV related nephropathies are due to the defects in collagen IV genes COL4A3, COL4A4, or COL4A5 and comprise a spectrum of phenotypes ranging from Alport Syndrome (AS) to its mild variants, termed as familial haematuria or thin basement membrane nephropathy. Classical AS is a progressive renal disease presenting with a triad of progressive hematuric nephritis and typical extra-renal complications, such as sensorineural hearing loss (SNHL) and variable ocular anomalies. The mode of inheritance in AS is X-linked in 85%, autosomal recessive in 15%, and autosomal dominant in rare cases. OBJECTIVES: This study aims to identify underlying mutation in multiple individuals from a large consanguineous Saudi family with inherited nephropathy, including our index patient who manifested all the features of classical AS. PATIENTS AND METHODS: Patients were diagnosed by nephrologists and clinical geneticists. All the individuals underwent clinical, audiological and ophthalmological evaluation. Blood samples were collected after written informed consent. DNA extraction, homozygosity mapping and PCR amplification followed standard methodologies. RESULTS: The disease locus was mapped to 2q36.3, where both COL4A3 and COL4A4 reside. Sanger sequencing of COL4A3 and COL4A4 revealed an underlying novel homozygous disease-causing COL4A4 mutation (c.2420delG; p.G807fsX60) in the affected proband. Considerable phenotypic variability segregating with this COL4A4 mutation in our study family is documented. The homozygous mutants were manifesting end-stage renal disease (ESRD) in their adolescence, while the heterozygous carrier members were presenting with considerable phenotypic heterogeneity ranging from intermittent hematuria to late onset ESRD. In addition, there is a relatively severe involvement of the ear (SNHL) and eye in the homozygotes than the heterozygotes. Fertility problems were also noted in both of the homozygous females. CONCLUSION: Identification of the causative mutation is an efficient strategy for conclusive molecular diagnosis in the patients and to establish genotype/phenotype correlation. It is important to study and evaluate asymptomatic carriers, to predict prognosis of the disease and to obviate the need for another renal biopsy in at-risk related family members. While an accurate genetic diagnosis of AS provides valuable information for genetic counseling in the extended family members, it can also facilitate future prenatal diagnosis and planning for pre-implantation genetic diagnosis.

ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi Arabian population.

Hearing impairment is the common human sensorineural disorder and is a genetically heterogeneous phenotype for which more than 100 genomic loci have been mapped so far. ILDR1 located on chromosome 3q13.33, encodes a putative transmembrane receptor containing an immunoglobulin-like domain. We used a combination of autozygosity mapping and candidate gene sequencing to identify a novel mutation in ILDR1, as a causative gene for autosomal-recessive non-syndromic hearing loss (arNSHL) in a consanguineous Saudi family with three affected children. Autozygosity mapping identified a shared region between the affected individuals encompassing ILDR1 on chromosome 3q13.12-3q22.1. Sequencing revealed homozygous 9 base pair duplication, resulting in an in-frame duplication of three amino acids p.(Asn109_Pro111dup). The mutation was segregating with the disease phenotype and is predicted to be pathogenic by SIFT and PROVEAN. The identified mutation is located in the immunoglobulin-type domain of the ILDR1 protein. In silico analysis using I-TASSER server and PyMOL offers the first predictions on the structural and functional consequences of this mutation. To our knowledge, this is the first ILDR1 mutation identified in a Saudi family. Identification of ILDR1 mutation in only one of 100 Saudi familial and sporadic individuals with hearing loss suggests that this mutation is unique to this family and that ILDR1 should be considered as a rare cause of congenital deafness among Saudi Arabian population. Our data also confirms the evidence for ILDR1 allelic heterogeneity and expands the number of familial arNSHL-associated ILDR1 gene mutations.

RP1 and retinitis pigmentosa: report of novel mutations and insight into mutational mechanism.

BACKGROUND/AIM: Retinitis pigmentosa (RP) is the commonest form of retinal dystrophy and is usually inherited as a monogenic trait but with remarkable genetic heterogeneity. RP1 is one of the earliest identified disease genes in RP with mutations in this gene known to act both recessively and dominantly although the mutational mechanism remains unclear. This study is part of our ongoing effort to characterise RP in Saudi Arabia at the molecular level. METHODS: Homozygosity mapping and candidate gene analysis. RESULTS: The authors have identified four novel mutations, all recessive, in a number of families with a typical RP phenotype. CONCLUSION: The distribution of these novel and previously reported RP1 mutations makes it challenging to describe a unifying mutational mechanism for dominant versus recessive RP1-related RP.