Combined CNV, haplotyping and whole exome sequencing enable identification of two distinct novel EYS mutations causing RP in a single inbred tribe.

Whole exome sequencing (WES) has become routine in clinical practice, especially in studies of recessive hereditary diseases in inbred consanguineous families, where homozygosity of a founder mutation is assumed. Multiple members of two consanguineous families of a single Bedouin tribe were diagnosed with apparently autosomal recessive/pseudo-dominant retinitis pigmentosa (RP). Affected individuals exhibited severe visual impairment with nyctalopia, marked constriction of visual fields, markedly reduced and delayed responses on electro-retinography (ERG) and eventual loss of central vision.

Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase.

Autosomal recessive Adams-Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams-Oliver syndrome genes, identifying a single-homozygosity ∼1.8-Mb novel locus common to affected individuals (LOD score 3.

High myopia caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2.

Autosomal-recessive high-grade axial myopia was diagnosed in Bedouin Israeli consanguineous kindred. Some affected individuals also had variable expressivity of early-onset cataracts, peripheral vitreo-retinal degeneration, and secondary sight loss due to severe retinal detachments. Through genome-wide linkage analysis, the disease-associated gene was mapped to ∼1.

Congenital glaucoma: CYP1B1 mutations in Israeli Bedouin kindreds.

Purpose: To investigate CYP1B1 gene mutations in Arab-Bedouin Israeli patients with primary congenital glaucoma (PCG).

Methods: Testing linkage to candidate genes using adjacent polymorphic markers and sequencing of genomic DNA samples by standard methods.

Results: In 9 of 11 unrelated affected Israeli Bedouin families, PCG was associated with homozygosity of 3 different CYP1B1 mutations.

Cardiovascular risk factors in the Bedouin population: management and compliance.

Background: Until three decades ago coronary heart disease and stroke were considered rare in the Israeli Bedouin population. Today, this population shows increasing high prevalence compared to the Jewish population.

Objectives: To evaluate the prevalence of diagnosed cardiovascular risk factors among Bedouins (hypertension, diabetes mellitus, dyslipidemia), and to assess compliance with follow-up tests and drug treatment.

Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway.

Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. We previously mapped LCCS2 to 6.4 Mb on chromosome 12q13 and have now narrowed the locus to 4.

Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway.

Lethal congenital contractural syndrome (LCCS) is a severe form of arthrogryposis. To date, two autosomal recessive forms of the disease (LCCS and LCCS2) have been described and mapped to chromosomes 9q34 and 12q13, respectively. We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder.

PLA2G6 mutation underlies infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum.

Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).

The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping.

Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a genetically heterogeneous multisystem disorder that causes severe visual impairment. Retinitis pigmentosa (RP), hypogonadism, digit and renal anomalies, obesity, and a variable degree of mental retardation characterize the disorder. Eight different loci have been identified on 2q31(BBS5), 3p13 (BBS3), 4q27 (BBS7), 11q13 (BBS1), 14q32 (BBS8), 15q22.

COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED).

Autosomal recessive Weissenbacher-Zweymuller syndrome (WZS) is a skeletal dysplasia characterized by rhizomelic dwarfism and severe hearing loss. Mutations in the COL11A2 gene have been implicated in causing the autosomal dominant form of this syndrome as well as non-ocular Stickler syndrome and the autosomal recessive syndrome otospondylomegaepiphyseal dysplasia (OSMED). In a consanguineous Bedouin tribe living in Southern Israel, five individuals affected by autosomal recessive WZS were available for genetic analysis.

Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13.

We have recently described a novel autosomal recessive disorder, lethal congenital contractural syndrome type 2 (LCCS2) (OMIM 607598), in a large Israeli Bedouin kindred. The phenotype, which is lethal in the neonatal period, is distinguished by the presence of a markedly distended urinary bladder. Association of LCCS2 to the known loci associated with arthogryposis was excluded.

Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3).

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Eight BBS loci have been mapped, and seven genes have been identified. BBS3 was previously mapped to chromosome 3 by linkage analysis in a large Israeli Bedouin kindred.

A new autosomal recessive congenital contractural syndrome in an Israeli Bedouin kindred.

We describe 23 cases with a syndrome of congenital contractures belonging to a large, inbred Israeli-Bedouin kindred. The phenotype described is similar to the Finnish type lethal congenital contracture syndrome yet differs in the following ways: by some additional craniofacial/ocular findings, by the lack of hydrops, multiple pterygia, and fractures, and by the normal duration of pregnancy. The major unique and previously undescribed clinical feature in our patients is a markedly distended urinary bladder as well as other urinary abnormalities.

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease.

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1.