Congenital glaucoma and CYP1B1: an old story revisited.

Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered.

Infantile Nephropathic Cystinosis: A Novel Mutation.

Cystinosis is a rare autosomal recessive metabolic disorder characterized by the accumulation of cystine in lysosomes, which results from defects in the carrier-mediated transport protein encoded by the gene. Infantile nephropathic cystinosis (INC) is one of the major complications of cystinosis. It is characterized by findings of Fanconi's syndrome within the first year of life.

Characterizing the morbid genome of ciliopathies.

Background: Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.

Results: We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum.

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract.

Pediatric cataract is highly heterogeneous clinically and etiologically. While mostly isolated, cataract can be part of many multisystem disorders, further complicating the diagnostic process. In this study, we applied genomic tools in the form of a multi-gene panel as well as whole-exome sequencing on unselected cohort of pediatric cataract (166 patients from 74 families).

Congenital hereditary endothelial dystrophy, not glaucoma, in a child with iris colobomas.

Corneal haze and elevated measured intraocular pressure in a young child with iris abnormalities are suggestive for glaucoma, but primary corneal disease is another possibility. We highlight the case of a 10-year-old boy with these clinical signs who was initially treated for glaucoma but in fact had congenital hereditary endothelial dystrophy, iris colobomas, and no glaucoma.

Exome-based case-control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy.

Unlabelled: Diabetic retinopathy (DR) is a common clinical expression of diabetes mellitus-induced vasculopathy and is a major cause of vision loss. Significant gaps remain in our understanding of the molecular pathoetiology of DR, and it is hoped that human genetic approaches can reveal novel targets especially since DR is a heritable trait. Previous studies have focused on genetic risk factors of DR but their results have been mixed.

Phenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis).

Purpose: To assess for phenotype-genotype correlations in families with recessive pediatric cataract and identified gene mutations.

Methods: Retrospective review (2004 through 2013) of 26 Saudi Arabian apparently nonsyndromic pediatric cataract families referred to one of the authors (A.O.

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.

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa.

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS).

Recessive mutations in LEPREL1 underlie a recognizable lens subluxation phenotype.

Purpose: To uncover the homozygous recessive gene mutation underlying familial lens subluxation and/or juvenile lens opacities in four sisters from a consanguineous family.

Methods: Prospective family study (clinical phenotyping; homozygosity-analysis-guided candidate gene testing).

Results: The proband was a 14-year-old girl with long-standing poor vision, bilateral temporal lens subluxation, lens opacities, and axial high myopia.

IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases.

Corneal enlargement without optic disk cupping in children with recessive CYP1B1 mutations.

Corneal enlargement during the first 3 years of life can be a sign of early childhood glaucoma and optic nerve head cupping is a useful confirmatory finding. We report 3 children with corneal enlargement without optic nerve head cupping who had recessive CYP1B1 mutations, the most common identifiable cause of primary congenital glaucoma. One child later developed unilateral Haab striae, still in the absence of optic disk cupping.

Lens subluxation and retinal dysfunction in a girl with homozygous VSX2 mutation.

Objective: To describe a unique lens subluxation phenotype in a child from a consanguineous family and to determine its genetic basis.

Methods: Ophthalmologic examination (including ocular biometry and electroretinography [ERG] for the proband) and autozygosity-analysis-guided exome sequencing for the family; confirmatory candidate gene sequencing in the family and ethnically matched controls.

Results: An otherwise healthy 3-year-old Saudi Arabian girl with poor vision since birth had smooth irides, lens subluxation, cone-rod dysfunction, and high myopia - features resembling Knobloch syndrome but differing in regard to direction of lens subluxation (superior rather than temporal) and the pattern of chorioretinal atrophy (without vitreous condensations or distinct macular atrophy).

Mutations in LRPAP1 are associated with severe myopia in humans.

Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations.

The syndrome of microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is caused by mutations in ADAMTS18.

One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18.

Childhood cone-rod dystrophy with macular cystic degeneration from recessive CRB1 mutation.

Purpose: To describe three siblings with childhood cone-rod dystrophy and macular cystic degeneration in a family with apparently variable phenotypes of CRB1-related recessive retinal dystrophy.

Methods: Ophthalmologic examination (including electroretinography (ERG), ocular coherence tomography (OCT), and intravenous fluorescein angiography when possible) and homozygosity analysis guided candidate gene testing.

Results: When the proband was evaluated at 7 years old for progressive visual loss, fundus exam was unremarkable (including no macular thickening clinically or by OCT) but ERG revealed cone-rod dysfunction with an electronegative waveform.

Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus.

Background: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population.

Objective: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology.

Materials And Methods: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus.

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.

Juvenile cataract morphology in 3 siblings not yet diagnosed with cerebrotendinous xanthomatosis.

Purpose: Cerebrotendinous xanthomatosis is a progressive neurodegenerative storage disease caused by recessive CYP27A1 mutations and is characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues, including the lens and brain. Oral chenodeoxycholic acid is preventive and can be therapeutic, but is not used optimally because the condition typically is diagnosed late or not at all. When affected children demonstrate lens opacities, ophthalmologists have the unique potential to facilitate earlier diagnosis and treatment by recognizing the juvenile cataract phenotype.

Congenital glaucoma with acquired peripheral circumferential iris degeneration.

Iris anomalies associated with congenital or early-childhood glaucoma include stable primary developmental abnormalities such as those associated with the Axenfeld-Rieger spectrum and aniridia. Secondary generalized iris atrophy from uncontrolled intraocular pressure is another potential iris finding in pediatric glaucoma. We document an unusual pattern of acquired peripheral circumferential iris degeneration in 2 unrelated children with otherwise-controlled congenital glaucoma.

CYP1B1 analysis of unilateral primary newborn glaucoma in Saudi children.

Nonsyndromic primary newborn glaucoma, the most severe form of primary congenital glaucoma, typically is bilateral and often the result of CYP1B1 mutations, particularly in certain consanguineous populations. Truly unilateral cases are uncommon and genetically not well studied. During a 9-year period, we tested 5 consecutive children with unilateral primary newborn glaucoma from Saudi Arabia, where CYP1B1 mutations are the cause for 91% of bilateral primary newborn glaucoma cases.