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Purpose: To report the results of molecular karyotyping for a dysmorphic girl withCYP1B1-negative primary congenital glaucoma from Saudi Arabia, whereCYPB1mutations account for over 90% of cases of primary congenital glaucoma and the remaining cases are idiopathic. Methods:CYP1B1sequencing in the affected child; high-resolution array comparative genomic hybridization (array CGH) of the affected child and both unaffected parents (Affymetrix Cytogenetics Whole-Genome 2.7M array; Affymetrix Inc., Santa Clara, CA, USA). Results: The girl did not harborCYP1B1mutation by Sanger sequencing. Array CGH revealed 2de novo7p heterozygous duplications (7p21 – 7p14, encompassing 223 genes, and 7p14-7p11.2, encompassing 225 genes) and a 4p homozygous microdeletion (4p14) encompassing one gene only,DTHD1. Conclusions: The fact that this dysmorphic girl is Saudi Arabian and hasCYP1B1-negative primary congenital glaucoma suggests that her glaucoma phenotype is related to herde novocopy number variation. Loss or gain of one or more of the genes encompassed in the identified chromosomal areas may be associated with primary congenital glaucoma and/or other observed phenotypic features. [ABSTRACT FROM PUBLISHER]

Purpose: To characterize the underlying genetic defect in otherwise healthy Saudi newborns with buphthalmos, including those with iris abnormalities. Methods: Prospective case series of affected Saudi Arabian probands who were referred for genetic counseling over a 4 year period. All had CYP1B1 sequencing. Selected patients with visible iris abnormalities had PAX6, FOXC1, and PITX2 sequencing. CYP1B1-negative patients had LTBP2 sequencing. Results: All 67 probands had corneal enlargement with variable haze/scarring evident to caregivers at birth; 46 had a family history of infantile or early childhood glaucoma. All families were consanguineous except for 6, 2 of which were endogamous. Eight probands had mild ectropion uveae with partial aniridia; 2 probands had thick scarred corneas that precluded careful iris examination. Homozygous or compound heterozygous CYP1B1 mutations were identified in 91% (61/67), including all 8 probands with ectopion uveae and partial aniridia. The common Saudi mutation p.G61E occurred in most cases (38 homozygous, 8 compound heterozygous). Four novel mutations were identified (p.N252K, p.V460E, p.S485F, p.N519D). No mutations were identified in the other screened genes. Conclusions: Newborn glaucoma on the Arabian Peninsula is typically CYP1B1-related even in the setting of developmental iris abnormality. Mild iris ectropion with partial aniridia in a newborn with glaucoma suggests mutations in CYP1B1 rather than in other genes associated with anterior segment dysgenesis. On the Arabian Peninsula p.G61E mutations are the major cause of newborn glaucoma but novel CYP1B1 mutations continue to be documented. The fact that the 9% of cases that were CYP1B1-negative did not have mutations in LTBP2 suggests that there exists at least 1 additional locus for this condition. [ABSTRACT FROM AUTHOR]

Schnyder corneal dystrophy is a rare dominant disorder mostly reported in Western and occasionally Asian populations. This report documents the condition in an affected family from the historically isolated Arabian Peninsula. A child and her mother had central crystalline keratopathy consistent with Schnyder corneal dystrophy. Diagnostic UB1AD1 testing revealed a known point mutation (c.361C>T, p.L121F) in both individuals. Available asymptomatic family members had normal ophthalmic examinations and did not have the mutation. Blood lipid profiles for the two patients revealed mildly elevated total cholesterol and low-density lipoproteins. This report documents Schnyder corneal dystrophy on the Arabian Peninsula and further confirms its relationship with heterozygous UB1AD1 missense mutation. [ABSTRACT FROM AUTHOR]

Purpose To describe the clinical features of patients from the Arabian Peninsula with Duane retraction syndrome (DRS). Methods Retrospective chart review of patients referred to the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia from 1982 to 2003 with a diagnosis of DRS. Patients having had prior strabismus surgery were excluded. Results Of 404 DRS patients, 347 (86%) were unilateral, 57 (14%) were bilateral, and 111 (27%) had amblyopia. There were 221 (55%) females and 182 (45%) males. The Huber classification was as follows: 315 (78%) Type I, 16 (4%) Type II, and 77 (19%) Type III. Of the 57 bilateral cases, 25 (44%) were female and 32 (56%) were male. Discussion Overall, the clinical features of DRS patients referred to a Riyadh eye hospital are similar to those reported in series throughout the world. However, our referred bilateral DRS patients are more commonly male. The clinical features of bilateral DRS deserve further worldwide study. [ABSTRACT FROM AUTHOR]

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. None of these children with unilateral primary newborn glaucoma harbored CYP1B1 mutations, suggesting that in this population the pathogenesis of unilateral disease differs from that of bilateral disease. [ABSTRACT FROM AUTHOR]

We describe siblings with familial primary juvenile glaucoma from a consanguineous Saudi Arabian family. The phenotype segregated with homozygous p.G61E CYP1B1 mutations while MYOC mutation was not detected, illustrating that mutations in CYP1B1 rather than mutation in MYOC can underlie familial primary juvenile glaucoma in certain populations. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Rhegmatogenous retinal detachments in pediatric vitreoretinopathies in Saudi Arabia," by S. T. Alshahrani et al, published in a previous issue is presented.

Purpose: Retinal arteriolar macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS) is a rare syndrome that to date has only been reported in Saudi Arabian families. All tested patients have been homozygous for a single IGFBP7 splice variant (NM_001553.2:c.830-1G>A). We report our experience with RAMSVPS in the United Arab Emirates., Methods: Retrospective case series., Results: Five affected individuals (two males and three females) from two unrelated Emirati families were known to our institution (age of first signs 6 months to 10 years of age, with one asymptomatic 6-year-old boy identified by sibling screening examination). Initial ophthalmic diagnoses had been Coats disease or traumatic retinal bleeding. Characteristic retinal arteriolar trunk beading and macroaneurysms led to the actual diagnosis of RAMSVPS. One child with esotropia at 6 months of age seemed to have unilateral Coats disease until retinal signs became apparent in the contralateral eye at 4 years old. One family consented to genetic testing, and both affected siblings were homozygous for the Saudi IGFBP7 splice variant (c.830-1G>A). The three children who underwent echocardiography were all confirmed to have cardiac valvular abnormalities (two supravalvular pulmonic stenosis and one tricuspid stenosis)., Discussion: The distinct ophthalmic phenotype of RAMSVPS is important to recognize because of systemic implications. Retinal findings can be misinterpreted as sequelae of trauma or Coats disease and can seem unilateral in very young children until changes in the contralateral eye become apparent years later. The homozygous IGFBP7 splice variant associated with the disease likely represents an ancestral founder effect for the Arabian Peninsula.

Although insects dominate the terrestrial fauna, sampling constraints and the poor taxonomic knowledge of many groups have limited assessments of their diversity. Passive sampling techniques and DNA-based species assignments now make it possible to overcome these barriers. For example, Malaise traps collect specimens with minimal intervention while the Barcode Index Number (BIN) system automates taxonomic assignments. The present study employs Malaise traps and DNA barcoding to extend understanding of insect diversity in one of the least known zoogeographic regions, the Saharo-Arabian. Insects were collected at four sites in three countries (Egypt, Pakistan, Saudi Arabia) by deploying Malaise traps. The collected specimens were analyzed by sequencing 658 bp of cytochrome oxidase I (DNA barcode) and assigning BINs on the Barcode of Life Data Systems. The year-long deployment of a Malaise trap in Pakistan and briefer placements at two Egyptian sites and at one in Saudi Arabia collected 53,092 specimens. They belonged to 17 insect orders with Diptera and Hymenoptera dominating the catch. Barcode sequences were recovered from 44,432 (84%) of the specimens, revealing the occurrence of 3,682 BINs belonging to 254 families. Many of these taxa were uncommon as 25% of the families and 50% of the BINs from Pakistan were only present in one sample. Family and BIN counts varied significantly through the year, but diversity indices did not. Although more than 10,000 specimens were analyzed from each nation, just 2% of BINs were shared by Pakistan and Saudi Arabia, 4% by Egypt and Pakistan, and 7% by Egypt and Saudi Arabia. The present study demonstrates how the BIN system can circumvent the barriers imposed by limited access to taxonomic specialists and by the fact that many insect species in the Saharo-Arabian region are undescribed., Competing Interests: The authors have declared that no competing interests exist.

Background: In Arabian children referred with retinal dystrophy, we have observed that a specific biallelic nonsense mutation in the gene encoding tubby-like protein 1 (TULP1, c.901C>T (p.Gln301*)) is recurrent. This makes the mutation and its associated childhood retinopathy particularly interesting for genetic diagnostic and, potentially, gene therapy approaches. We characterise the ophthalmic phenotype associated with recessive p.Gln301* mutation in TULP1 and assess the mutation for single founder effect., Methods: Retrospective consecutive case series (2011-2014) of 10 Arabian children (8 families) homozygous for the p.Gln301* mutation (detected after next-generation sequencing) and 12 ethnically matched controls. TULP1 haplotypes were constructed by analysis of TULP1 intragenic single nucleotide polymorphisms from next-generation sequencing data and genotyping of gene-flanking polymorphic microsatellite markers., Results: All 10 children (2-8 years old; mean 5.2, median 6) had nystagmus since soon after birth, a grossly normal posterior pole other than arteriolar attenuation, peripheral mottling with apparent evolution to bone spicules, and hyperopia. Rod function was non-recordable while cone function was present (albeit depressed and delayed); however, repeat electroretinogram years later in two children revealed loss of recordable cone function. Autofluorescence showed a hyper-fluorescent ring around the fovea while central optical coherence tomography was within normal limits. A specific haplotype was associated with p.Gln301* and was not present in controls., Conclusions: The TULP1 allele p.Gln301* represents a founder mutation on the Arabian Peninsula and is associated with a recognisable congenital recessive rod-cone dystrophy phenotype in the homozygous state., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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.

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Pediatric cataract is an important preventable blinding disease. Previous studies have estimated 10-25% of cases to be genetic in etiology., Methods: In an effort to characterize the genetics of cataract in our population, we have conducted a comprehensive clinical and genomic analysis (including autozygome and exome analysis) on a series of 38 index patients., Results: Pediatric cataract is genetic in at least 79% of the study families. Although crystallins accounted for most of the mutant alleles, mutations in other genes were encountered, including recessive mutations in genes that usually cause the disease in a dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified., Conclusion: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies.

Joubert syndrome (JS) is a ciliopathy that is defined primarily by typical cerebellar structural and ocular motility defects. The genetic heterogeneity of this condition is significant with 16 genes identified to date. We have used a combination of autozygome-guided candidate gene mutation analysis and exome sequencing to identify the causative mutation in a series of 12 families. The autozygome approach identified mutations in RPGRIP1L, AHI1, TMEM237, and CEP290, while exome sequencing revealed families with truncating mutations in TCTN1 and C5ORF42. Our study, the largest comprehensive molecular series on JS, provides independent confirmation of the recently reported TCTN1, TMEM237, and C5ORF42 as bona fide JS disease genes, and expands the allelic heterogeneity of this disease., (© 2012 Wiley Periodicals, Inc.)

Aim: To clinically and genetically characterise central pulverulent cataract in a consecutive cohort of children from the Arabian Peninsula who were referred for ophthalmic evaluation., Methods: Ophthalmic examination, homozygosity mapping in a consanguineous family and candidate gene analysis., Results: All 16 children (4-16 years old, mean 9 years; seven girls and nine boys from 10 families) had bilateral central nuclear dust-like lenticular opacities. Two patients (one family) had cortical riders and six had associated strabismus. Cycloplegic retinoscopy was usually hyperopic (13/16; right eye spherical equivalent +0.50 to +6.25 dioptres, mean +3.50) but was sometimes myopic (3/16; right eye spherical equivalent -0.50 to -11.75, mean -6.50). In children with amblyopia (5/16), the cause was significant uncorrected ametropias rather than the lens opacities. Three patients had uncomplicated unilateral cataract surgery suggested by an outside second opinion that did not improve best-corrected visual acuity. Homozygosity mapping for one consanguineous family suggested the candidate gene CRYBB1. Sequencing of this gene revealed a homozygous c.171del mutation (p.N58Tfs*107) with a shared haplotype in all 16 children. In asymptomatic carrier parents from five of the six families available for careful slit-lamp examination, occasional central dot lenticular opacities were documented., Conclusions: Central pulverulent cataract in this consanguineous population does not significantly impact visual acuity during early childhood, can be associated with significant ametropias (with amblyopia and/or strabismus) and is specific for a homozygous CRYBB1 founder mutation. Primary management in children is typically spectacle correction based on cycloplegic retinoscopy to treat significant refractive error rather than paediatric cataract surgery.

Purpose: To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus., Methods: Prospective clinical examination and linkage analysis., Results: three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes., Discussion: Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype.

Purpose: To determine the genetic and genomic alterations underlying classic aniridia in Saudi Arabia, a region with social preference for consanguineous marriage., Methods: Prospective study of consecutive patients referred to a pediatric ophthalmologist in Saudi Arabia (2005-2009). All patients had paired box gene 6 (PAX6) analysis (sequencing and multiplex ligation-dependent probe amplification analysis if sequencing was normal). If PAX6 analysis was negative, the following were performed: candidate gene sequencing (forkhead box C1 [FOXC1], paired-like homeodomain transcription factor 2 [PITX2], cytochrome P450, family 1, subfamily B [CYP1B1], paired-like homeodomain transcription factor 3 [PITX3], and v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog [MAF]) and molecular karyotyping by array competitive genomic hybridization (250K single nucleotide polymorphism (SNP) arrays)., Results: All 12 probands (4 months-25 years of age; four boys and eight girls) had lens opacity and foveal hypoplasia in addition to no grossly visible iris. Four cases were familial. All cases were products of consanguineous unions except for three, one of which was endogamous. Heterozygous PAX6 mutations (including two novel mutations) were detectable in all but two cases, both of which were sporadic. In one of these two cases, the phenotype segregated with homozygosity for a previously-reported pathogenic missense FOXC1 variant (p.P297S) when homozygosity for chromosome 11q24.2 deletion (chr11:125,001,547-125,215,177 [rs114259885; rs112291840]) was also present. In the other, no genetic or genomic abnormalities were found., Conclusions: The classic aniridia phenotype in Saudi Arabia is typically caused by heterozygous PAX6 mutations, even in the setting of enhanced homozygosity from recent shared parental ancestry. For PAX6-negative cases, interaction between missense variation in an anterior segment developmental gene and copy number variation elsewhere in the genome may be a potential mechanism for the phenotype.

Purpose: Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists., Methods: Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010., Results: All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3., Conclusions: The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci).

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.

Purpose: To describe phenotyping and linkage analysis results for available members from a consanguineous nuclear family with hereditary congenital strabismus., Methods: Both parents and all 12 children underwent clinical examination. Available affected and several unaffected family members had venous blood sampling for DNA extraction and 10K single nucleotide polymorphism (SNP) genotyping (Affymetrix Gene Chip® Human). Multipoint logarithm of the odds (LOD) score calculations were performed assuming an autosomal recessive mode of inheritance with 100% penetrance and disease allele frequency of 0.01%., Results: Three children had non-syndromic large-angle infantile esotropia without significant hyperopia. A fourth child had left esotropic Duane retraction syndrome. A fifth child who had esotropia in the setting of prematurity and childhood poliomyelitis was excluded from the analysis. A sixth child had keratoconus and was excluded. Both parents and the remaining 6 children had no significant orthoptic or ophthalmic findings. Using linkage analysis including the 4 esotropic children, disease loci were mapped to regions on chromosomes 3p26.3-26.2 and 6q24.2-25.1 using multipoint linkage analysis with LOD scores of 3.18 and 3.25 respectively. Linkage to these regions persisted when the esotropic Duane retraction syndrome patient was excluded from the linkage analysis (LOD scores of 2.00 and 2.32, respectively)., Conclusions: Non-syndromic infantile esotropia could be related to susceptibility loci on chromosomal regions 3p26.3-26.2 and 6q24.2-25.1 and may share alleles that underlie Duane retraction syndrome.

Background: Cystinosis is an autosomal recessive disease characterized by impaired transport of free cystine out of lysosomes with resulting renal and ophthalmic manifestations. Mutations in CTNS, encoding cystinosin, are the only known cause of this autosomal recessive disorder with more than 85 different mutations described so far., Purpose: To identify CTNS mutations in Arab cystinosis patients., Methods: In this study, we have analyzed the mutational spectrum of CTNS in a population of 21 patients from 13 families of Arab origin. The entire coding region and flanking intronic regions of CTNS were analyzed by direct sequencing., Results: Eight mutations were identified, four of which are novel (c.530A>G, c.681G>A, 1013T>G, and c.1018_1041del)., Conclusion: These alleles will provide the basis for routine molecular diagnosis of cystinosis in the region.

Purpose: To catalog mutations that underlie retinitis pigmentosa (RP) in Saudi Arabia using a representative sample., Methods: Fifty-two patients with RP were recruited and their homozygosity mapping, with or without linkage analysis, was used to suggest the causative genes followed by bidirectional sequencing., Results: Mutations were identified in 94% of our study cohort, including seven that were novel., Conclusions: Homozygosity mapping is an extremely robust approach in the study of retinitis pigmentosa in the setting of high rates of consanguinity. BBS3 mutations can rarely present as nonsyndromic RP.

Purpose: To determine the extent of allelic, and possibly locus, heterogeneity in congenital hereditary endothelial dystrophy (CHED, MIM 217700) in patients from a highly consanguineous Saudi population., Methods: Homozygosity was determined at the solute carrier family 4, sodium bicarbonate transporter-like, member 11 (SLC4A11) locus followed by full sequencing of SLC4A11 in 10 patients representing seven unrelated families., Results: All 10 patients were homozygous at the SLC4A11 locus. Seven mutations were identified, five of which are novel, including one likely intronic splicing enhancer mutation, all predicted to result in reduction or loss of bicarbonate transporter-related protein 1 (BTR1)., Conclusions: In this small cohort, no evidence was found of genetic heterogeneity in CHED and that loss of BTR1 function is the most likely mutational mechanism.

Purpose: To assess for gammaD-crystallin (CRYGD) mutation in 2 Saudi patients with cerulean cataract and in a brother of one of the patients who had coralliform cataract., Methods: Patients and all of their available relatives underwent ophthalmic examination and subsequent sequencing of the candidate gene CRYGD., Results: In the first family, a 4-year-old boy with bilateral cerulean cataract and his 6-year-old brother with similar bluish lens discoloration but in a coralliform pattern were heterozygous for the p.P23T CRYGD mutation. Their father and 2 older brothers, all of whom underwent childhood cataract surgery, also harbored the mutation while the 2 asymptomatic immediate family members did not. In the second family, a 7-year-old girl with bilateral cerulean cataract was heterozygous for the same CRYGD mutation. Details of her family history were limited. The patients in the two families shared a common disease haplotype., Conclusions: This first report of p.P23T CRYGD mutation underlying cerulean cataract in the Saudi population strongly supports the mutation's relation with the phenotype. Coralliform cataract can represent variable expressivity for the same mutation rather than a distinct entity.

The increased frequency of rare autosomal recessive conditions in genetically isolated populations is a well-established phenomenon. This genetic isolation is invoked as an explanation when one particular mutation is the sole or most frequent mutation observed in a given population and is referred to as the founder effect. This trend of allelic homogeneity is contrasted by an opposite trend when the consanguinity factor is in play. Independent of endogamy at the population level, a consanguineous union is sufficient to render homozygous a percentage of the genome that is directly correlated with the degree of consanguinity. Assuming the gene in question has a normal mutation rate, the resulting homozygosity will inevitably include different defective alleles of that gene. By reporting four novel alleles, we use Alström disease to exemplify the interesting observation of allelic heterogeneity for a very rare autosomal recessive disorder in a highly inbred population. While we frequently assume founder effect in inbred populations, this report should serve to remind us of the powerful effect of the consanguinity factor, a common confounding variable among some of those populations.

Introduction: Ataxia telangiectasia (AT) is a recessive neurodegenerative disease due to a faulty repair mechanism for breaks in double-stranded DNA (ATM mutation). Ophthalmic features of AT include conjunctival telangiectasia, strabismus, saccadic dysfunction with head thrusts, and convergence insufficiency. Ataxia telangiectasia-like syndrome (ATLD) is a more recently recognized condition due to homozygous mutation in MRE11, a gene also involved in the cellular repair response to double-stranded DNA breaks; ophthalmic features of ATLD are not well described. The purpose of this article is to describe the ophthalmic features of ATLD., Methods: Full ophthalmologic and orthoptic evaluations were obtained in 13 individuals: 10 previously reported ATLD patients, an additional related ATLD patient, and 3 nonaffected relatives. All individuals were from three unrelated consanguineous Saudi Arabian families harboring an MRE11 mutation (W210C). Age range was from 2 to 40 years of age., Results: No affected patient had structural ocular abnormality (eg, conjunctival telangiectasia), manifest strabismus at distance, or duction limitation. All but one (the youngest) had saccadic dysfunction (without head thrusts). Most patients had abnormal convergence. Older patients had nystagmus with abnormalities in smooth pursuit and vestibular ocular reflex. All patients had cerebellar atrophy by neuroimaging and slowly progressive ataxia. The unaffected heterozygous relatives had unremarkable ophthalmic and neurologic examinations., Conclusions: Saccadic dysfunction without head thrusts and convergence abnormality are common in ATLD secondary to homozygous W210C MRE11 mutation. Older patients have nystagmus with abnormalities in smooth pursuit and vestibular ocular reflex. Eye movement control systems apparently deteriorate with time in this rare neurological disease. Ophthalmic features of AT that were not observed in any of our ATLD patients include conjunctival telangiectasia, head thrusting, and manifest strabismus at distance.

Purpose: To assess for KIF21A mutation in the first two reported Saudi Arabian families with the classic phenotype of congenital fibrosis of the extraocular muscles type I (CFEOM1)., Methods: Clinical examination and genetic testing by amplification refractory mutation system (ARMS) assay for KIF21A R954W, the most common KIF21A mutation worldwide., Results: Clinical examination was consistent with classic CFEOM1 in both Family A and Family B. All participating patients (one child from Family A and four adults from Family B) were heterozygous for KIF21A R954W mutation., Conclusions: CFEOM1 is rare is Saudi Arabia as it is in the rest of the world. The finding of R954W mutation in the historically isolated population of the Arabian Peninsula confirms that R954 is a "hotspot" for KIF21A mutation.

Background: Although idiopathic sixth (abducens) nerve paresis of childhood typically resolves within a few months, the paresis recurs in a minority of cases. The purpose of this study is to describe clinical features at presentation that are associated with later recurrence., Methods: Retrospective literature review and novel case report., Results: Thirty-five articles were reviewed, revealing 54 nonrecurrent and 41 recurrent cases. One previously unreported recurrent case is also included in our review. Patients with recurrence were typically girls (p < 0.05) and were typically affected in the left eye (p < 0.05). All children who initially presented under 14 months of age and/or whose initial presentation was associated with vaccination developed recurrence. Seventy-three percent of second episodes occurred within one year of initial presentation. No children who initially presented after 12 years of age developed recurrence., Conclusions: When an otherwise normal child is diagnosed with idiopathic sixth nerve paresis, clinical features suggestive of later recurrence are female gender, left eye involvement, younger age, and recent vaccination. Recurrence is less likely if it has not occurred within one year of the initial event.

Hypoparathyroidism-retardation-dysmorphism (HRD; Sanjad-Sakati Syndrome; Online Mendelian Inheritance in Man [OMIM] #241410) is a rare recessive syndrome predominantly seen on the Arabian Peninsula and characterized by congenital hypoparathyroidism, intrauterine growth retardation, mental retardation, seizures, and a typical facial dysmorphism (prominent forehead, deep-set eyes, and abnormal external ears).(1,2) To date, the same homozygous deletion in TBCE (155-166del) has been reported in all Saudi Arabian patients with HRD(1) as well as in all Saudi Arabian patients with Kenny-Caffey syndrome (OMIM #244460),(1) a syndrome with a phenotype that resembles that of HRD but is characterized by the presence of normal intelligence, late closure of the anterior fontanelle, macrocephaly, and postnatal (rather than prenatal) growth retardation.(1,3) Nanophthalmos and corneal opacity have been documented in Kenny-Caffey syndrome patients,(4) but ocular disease has not been well-described in HRD. We describe the ocular features of four Saudi Arabian HRD children referred to our institution for ocular complaints noted by their parents.

Objective: To characterize the molecular genetics of clinically diagnosed recessive cornea plana in the Kingdom of Saudi Arabia and establish the presence of common or limited founders (ancestors who originally harbored the disease-causing mutation) in the country's historically isolated population., Design: Prospective interventional case series., Participants: Twelve affected patients from apparently unrelated Saudi Arabian nuclear families with clinically diagnosed recessive cornea plana., Methods: Clinical ophthalmic examination and venous blood sampling for DNA sequencing., Main Outcome Measures: Age, gender, keratometry, best-corrected visual acuity, ocular alignment, cycloplegic refraction, significant findings of a complete ophthalmic examination, and keratocan gene (KERA) haplotype analysis., Results: All 12 individuals had classic phenotypic features of recessive cornea plana and were homozygous for 1 of 2 KERA mutations--a novel frameshift mutation (1634delC) or a previously reported nonsense mutation (R313X). Haplotype analysis was consistent with a separate distinct common founder effect for each instance. An additional Saudi KERA mutation (R279X) has been reported previously in one family., Conclusion: Specific for mutation in KERA, the ophthalmic phenotype of recessive cornea plana does not significantly vary with different KERA mutations. The occurrence of a rare inherited disease in a historically isolated population is not always due to a single common founder effect; it may be explained by cultural preferences such as consanguinity (intrafamilial marriage) and endogamy (intratribal marriage), which enhance expression of recessively inherited diseases.

Purpose: To describe the clinical characteristics of bilateral Duane syndrome., Methods: Retrospective medical record review (1982 to 2003) for patients with a diagnosis of Duane syndrome (examined by a pediatric ophthalmologist) who were bilaterally affected and had no prior ocular surgery. Data collected included type of Duane syndrome, gender, family history for strabismus, abnormal head position, versions, strabismus measurements, associated ocular and/or nonocular abnormalities, and amblyopia status., Results: Of 270 patients with the diagnosis of Duane syndrome, 37 (14%) were bilaterally affected. None had ocular surgery prior to referral. Twenty-two (59%) were male, 35 (95%) had the same Duane syndrome type in both eyes, 29 (78%) had strabismus in primary position, 9 (24%) had ocular and nonocular congenital abnormalities, 6 (16%) had amblyopia, and 8 (22%) had a recorded strabismus family history., Conclusions: Unlike unilateral Duane syndrome, bilateral Duane syndrome may be more common in males and associated with a higher prevalence of strabismus in primary gaze position. The prevalences of amblyopia, positive strabismus family history, and associated congenital abnormalities in this series of bilateral cases is similar to the reported prevalence.