A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B.

Background: Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA.

Methods: Clinical phenotyping of two consanguineous families followed by combined autozygome/exome analysis.

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).

ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).

Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction.

Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome.

We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl β-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins.

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.

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.

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.

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.

Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.

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.

Genomic analysis of pediatric cataract in Saudi Arabia reveals novel candidate disease genes.

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.

Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus.

Hereditary forms of cataract are genetically heterogeneous. Mutations in crystallin genes account for most Mendelian forms, but identification of other cataract genes has provided insights into additional molecular mechanisms that control lens transparency. In a multiplex consanguineous family with isolated congenital cataract, we identified a novel autosomal recessive cataract locus on 7q33-q36.

The distinct ophthalmic phenotype of Knobloch syndrome in children.

Background: Knobloch syndrome is defined as a triad of occipital defect, high myopia and vitreo-retinal degeneration (often with later retinal detachment); however, the ocular phenotype is not well defined. This report characterises eye findings of the syndrome in children with genetically confirmed disease.

Methods: Case series of Saudi children with previously documented homozygous mutations in COL18A1 or ADAMTS18.

In search of triallelism in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease.

Clinical and molecular analysis of children with central pulverulent cataract from the Arabian Peninsula.

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.

Phenotype-genotype correlation in potential female carriers of X-linked developmental cataract (Nance-Horan syndrome).

Purpose: To correlate clinical examination with underlying genotype in asymptomatic females who are potential carriers of X-linked developmental cataract (Nance-Horan syndrome).

Methods: An ophthalmologist blind to the pedigree performed comprehensive ophthalmic examination for 16 available family members (two affected and six asymptomatic females, five affected and three asymptomatic males). Facial features were also noted.

Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia.

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.

Identification of ADAMTS18 as a gene mutated in Knobloch syndrome.

Background: Knobloch syndrome (KS) is a developmental disorder characterised by occipital skull defect, high myopia, and vitreo-retinal degeneration. Although genetic heterogeneity has been suspected, COL18A1 is the only known KS disease gene to date.

Objective: To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study.

Novel recessive BFSP2 and PITX3 mutations: insights into mutational mechanisms from consanguineous populations.

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.