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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.K.) and for which recessive gene mutations were identified., Results: Fifteen different homozygous recessive gene mutations were identified in the 26 consanguineous families; two genes and five families are novel to this study. Ten families had a founder CRYBB1 deletion (all with bilateral central pulverulent cataract), two had the same missense mutation in CRYAB (both with bilateral juvenile cataract with marked variable expressivity), and two had different mutations in FYCO1 (both with bilateral posterior capsular abnormality). The remaining 12 families each had mutations in 12 different genes (CRYAA, CRYBA1, AKR1E2, AGK, BFSP2, CYP27A1, CYP51A1, EPHA2, GCNT2, LONP1, RNLS, WDR87) with unique phenotypes noted for CYP27A1 (bilateral juvenile fleck with anterior and/or posterior capsular cataract and later cerebrotendinous xanthomatosis), EPHA2 (bilateral anterior persistent fetal vasculature), and BFSP2 (bilateral flecklike with cloudy cortex). Potential carrier signs were documented for several families., Conclusions: In this recessive pediatric cataract case series most identified genes are noncrystallin. Recessive pediatric cataract phenotypes are generally nonspecific, but some notable phenotypes are distinct and associated with specific gene mutations. Marked variable expressivity can occur from a recessive missense CRYAB mutation. Genetic analysis of apparently isolated pediatric cataract can sometimes uncover mutations in a syndromic gene. Some gene mutations seem to be associated with apparent heterozygous carrier signs.

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. Four years later repeat examination was significant for bilateral macular cystic degeneration and immediate family members were evaluated. Both the older sister (15 years old) and the younger brother (7 years old) had cone-rod dystrophy with macular cystic degeneration. Both the father (45 years old) and mother (35 years old) had had early adult-onset nyctalopia with later eventual loss of central vision; examination revealed dystrophic retinas with mostly peripheral clumped and/or nummular pigment and macular atrophy. ERG for both the older sister and younger brother confirmed cone-rod dysfunction (without an electronegative waveform) and was non-recordable for both the parents. Homozygosity analysis guided candidate gene analysis and confirmatory Sanger sequencing for the family uncovered a homozygous CRB1 mutation (c.80G > T [p.Cys27Phe]) in affected family members., Conclusions: The phenotypic spectrum of recessive CRB1 mutation includes childhood cone-rod dystrophy with macular cystic degeneration and the associated ERG can be electronegative.

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.

Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjögren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Designating mutations as recessive or dominant is a function of the effect of the mutant allele on the phenotype. Genes in which both classes of mutations are known to exist are particularly interesting to study because these mutations typically define distinct pathogenic mechanisms at the molecular level., Methods: We studied two consanguineous families with different eye phenotypes and used a combination of candidate gene analysis and homozygosity mapping to identify the underlying genetic defects., Results: In one family, a novel BFSP2 mutation causes autosomal recessive diffuse cortical cataract with scattered lens opacities, and in another, a novel PITX3 mutation causes an autosomal recessive severe form of anterior segment dysgenesis and microphthalmia., Conclusion: We show that BFSP2 and PITX3, hitherto known to cause eye defects only in a dominant fashion, can also present recessively. The likely null nature of both mutations and lack of manifestation in heterozygotes strongly argues for a mechanism other than loss of function in the previously reported dominant mutations in these two genes. Thus, study of consanguineous populations has the additional advantage of not only identifying novel recessive genes but also defining the mutational mechanism of dominant disorders.

Purpose: To clinically and genetically characterize a distinct phenotype of congenital megalocornea (horizontal corneal diameter ≥13 mm) with secondary glaucoma from spherophakia and/or ectopia lentis during childhood in affected Saudi families., Methods: Clinical exam, homozygosity scan, and candidate gene analysis., Results: From 2005 to 2010, eight affected individuals from three consanguineous families were identified. In addition to congenital megalocornea, affected children presented with secondary glaucoma from spherophakia and/or ectopia lentis. One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood. Older individuals had phenotypes that would have suggested prior uncontrolled primary congenital/infantile glaucoma had past ophthalmic and/or family histories not been available. Homozygosity mapping performed for the first two families suggested the candidate gene latent transforming growth factor-beta-binding protein 2 (LTBP2), which when sequenced revealed a novel homozgyous mutation that segregated with the phenotype in each family (p.S338PfsX4 [c.1012delT], p.Q1619X[(c.4855C>T]). LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A])., Conclusions: Congenital megalocornea with childhood secondary glaucoma from spherophakia and/or ectopia lentis is a distinct condition caused by recessive LTBP2 mutations that needs to be distinguished from buphthalmos secondary to primary congenital/infantile glaucoma because typical initial surgical treatment is lens removal in the former and angle surgery in the latter. Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.

Objectives: To describe a unique pattern of helicoid subretinal fibrosis associated with a novel recessive NR2E3 mutation and to highlight how examination of the proband's affected relative allowed appropriate genetic testing., Design: Interventional family study (ophthalmic examination and candidate gene testing)., Results: The proband (mother), who complained of poor vision since early childhood, had bilateral helicoid subretinal fibrosis mostly involving the macula. Two children were symptomatic; one had ophthalmic findings similar to her mother while the second had macular retinoschisis, retinal pigment epithelium changes, and refractive accommodative esotropia. The father and third child were asymptomatic and had unremarkable ophthalmic examination findings. Based on the findings in the second symptomatic child, NR2E3 analysis was performed, which revealed homozygosity for a novel mutation, p.S44X, in all 3 affected individuals and heterozygosity for the mutation in both asymptomatic individuals., Conclusion: Helicoid subretinal fibrosis is another potential phenotypic manifestation of recessive NR2E3 mutation., Clinical Relevance: Examination of affected relatives can be helpful in guiding molecular genetic testing for hereditary eye disease when the proband's diagnosis is unclear.

Introduction: Reports from around the world confirm that heterozygous PAX6 mutation is the major cause of hereditary aniridia (with a classic phenotype of iris hypoplasia, keratopathy, lens opacity, and foveal hypoplasia). However, genotype/phenotype reports are lacking from the Arabian Peninsula, a historically isolated region with a relatively high incidence of recessive disease and thus a potential for phenocopy and pseudodominance. The purpose of this study to assess for PAX6 mutation in two unrelated families with classic hereditary aniridia from the Arabian Peninsula., Methods: Interventional cases series of two unrelated affected Saudi Arabian families. Available family members underwent ophthalmic examination and venous blood sampling for PAX6 sequencing., Results: The pedigrees of both families suggested dominant (or pseudodominant) inheritance of the classic aniridia phenotype. Affected individuals in Family #1 were heterozygous for a novel frameshift PAX6 mutation (c.delA1294). Affected individuals in Family #2 had heterozygosity for a commonly-reported PAX6 nonsense mutation (p.Arg240X)., Conclusions: PAX6 haploinsufficiency, the major cause of classic hereditary aniridia worldwide, is also associated with the phenotype in two different families from the Arabian Peninsula. Homozygosity by descent is not expected to affect genotype/phenotype correlation for the classic phenotype.

Purpose: To correlate ophthalmic findings with carrier status for a severe Norrie disease (ND) gene mutation (C95F)., Design: Prospective interventional case series., Participants: Six potential carriers and 1 obligate carrier from a family harboring the mutation., Methods: An ophthalmologist blind to the pedigree performed a full ophthalmic examination for the 7 asymptomatic family members. A peripheral blood sample was collected from each for ND gene sequencing., Main Outcome Measures: Ophthalmic examination findings (with attention to the presence or absence of retinal findings) and results of ND gene sequencing., Results: Three carriers were identified by molecular genetics, and all 3 of them had peripheral retinal abnormality. However, 3 of the 4 genetically identified noncarriers also exhibited peripheral retinal abnormality. Two of these noncarriers with retinal findings were the offspring of a confirmed noncarrier. The genetically identified noncarrier with a normal peripheral retinal examination was the daughter of an obligate carrier., Conclusions: The presence of peripheral retinal changes was not useful for carrier prediction in a family harboring ND. There are likely additional loci responsible for phenotypic expression.