A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness.

Using a candidate gene approach, we identified a novel human gene, OTOF, underlying an autosomal recessive, nonsyndromic prelingual deafness, DFNB9. The same nonsense mutation was detected in four unrelated affected families of Lebanese origin. OTOF is the second member of a mammalian gene family related to Caenorhabditis elegans fer-1. It encodes a predicted cytosolic protein (of 1,230 aa) with three C2 domains and a single carboxy-terminal transmembrane domain. The sequence homologies and predicted structure of otoferlin, the protein encoded by OTOF, suggest its involvement in vesicle membrane fusion. In the inner ear, the expression of the orthologous mouse gene, mainly in the sensory hair cells, indicates that such a role could apply to synaptic vesicles.

Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients.

Familial Mediterranean fever is an autosomal recessive disorder characterised by episodic fever, abdominal and pleuritic pain, serositis and arthritis. The FMF gene (MEFV) has been mapped to chromosome 16p13.3 and generates a protein found exclusively in granulocytes. Seventeen mutations have been reported up to the present in FMF patients. This study involves the screening of 14 mutations in 42 Jordanian patients by two methods: RFLP and ARMS. The most frequent mutations were M694V and V726A (20% and 14% of the alleles respectively), followed by M680I and E148Q (9.5% and 7% of the alleles respectively). The A744S mutation accounts for 2.5% and the M694I, T267I and F479L mutations account each for 1% of the alleles. E167D, R761H, P369S, I692del and M694del mutations were not found in this population. Forty-four percent of the alleles did not have any of the 14 mutations. The results show the diversity and the frequency of the mutations in the Jordanian patients, and open the way for further investigations on patients diagnosed to have FMF and in whom no mutations were found. Hum Mutat 15:384, 2000.

Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population.

Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

Identification of a locus on chromosome 7q31, DFNB14, responsible for prelingual sensorineural non-syndromic deafness.

In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family affected with a prelingual profound sensorineural isolated form of deafness. Segregation analysis resulted in a linkage with locus D7S554 to locus D7S2459 on 7q31, with a maximum lod score of 6.3. The causative gene was mapped to a 15 cM interval extending from D7S527 to D7S3074 (on the telomeric side). The distal limit of this interval could be located between D7S496 and D7S3074 which are the closest polymorphic loci flanking the gene underlying Pendred syndrome (PDS) on the centromeric and on the telomeric sides, respectively. To eliminate PDS as a candidate gene, its 21 exons were sequenced. No mutation was detected. This study therefore reports the identification of a novel locus, DFNB14, on chromosome 7q31, in a position proximal to PDS.

A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36.

Deafness is the most frequent sensorineural defect in children. The vast majority of the prelingual forms of isolated deafness are highly genetically heterogeneous with an autosomal recessive mode of inheritance. Using linkage analysis, we have mapped the gene responsible for a severe progressive sensorineural hearing loss, DFNB13, segregating in a large consanguineous family living in an isolated region in northern Lebanon. A maximum lod score of 4.5 was detected for markers D7S661-D7S498. Recombination events and homozygosity mapping by descent define a 17 cM gene interval in the chromosome region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3.

We report on a Lebanese family in which two maternal cousins suffered and died very early in life from cardiac malformations. Both presented with a transposition of the great arteries associated with one or several other cardiac defects. Various minor midline defects were also observed, but there were no situs abnormalities other than a persistent left superior vena cava in one. A maternal uncle of these two babies was born cyanotic and died on the third post-natal day. Analysis of the ZIC3 gene, revealed the presence of a mutation in the second exon leading to a truncation of the protein. Surprisingly, another maternal uncle of the two affected cousins also had the mutation but was not clinically affected. To our knowledge, this is the first instance of incomplete penetrance in a male for a mutation in a chromosome X gene.

Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations.

Familial Mediterranean Fever (FMF) is a recessively inherited disorder, characterized by episodic fever, abdominal and arthritic pain, as well as other forms of inflammation. Some FMF patients present higher IgD serum levels, and it is not yet known whether such an elevation is related to specific genotypes or correlated with a specific phenotype. In order to evaluate the association between known FMF-related mutations and IgD levels in confirmed patients, as well as the correlation between those levels and the presence of specific clinical signs, genotypic analysis and IgD plasma measurements were performed for 148 Lebanese and Jordanian FMF patients. Most common mutational patterns were M694V heterozygotes (19%) and homozygotes (17%), and V726A heterozygotes (18%) and homozygotes (5%), with an additional 11% combining both mutations. Twenty-one patients had higher IgD levels (superior to 100 microg/ml). The risk for higher IgD levels was significantly associated with M694V homozygote status (OR = 6.25) but not with heterozygotic one (OR = 1). Similarly, the risk for higher IgD was also found with V726A homozygotes (OR = 2.2) but not with heterozygotes (OR = 1.05). The use of colchicine was not statistically associated with IgD levels. Clinically, hyper IgD was also found significantly associated with arthritis (OR = 18). Thus, homozygotic status for M694V, and to a lesser extent V726A, is associated with increased risk for higher IgD plasma levels, regardless of colchicine use. Elevated IgD plasma levels are also correlated with the severity of FMF manifestations, and especially with arthritis.

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.

Genetic diseases in Lebanon.

Lebanon has a high incidence of common and rare genetic diseases, due probably to the mosaic different ethnic origins and the high rate of consanguineous marriages in certain communities. Two major investigations, exploring the genetic structure of the Lebanese population, indicated the population to be caucasiods (though Oriental traits were found). These investigations involved studies of dermatoglyphics, and type and distribution of genetic markers and protein variants. Recorded genetic diseases, some characteristic of ethnic group or particular to a geographic region include familial paroxysmal polyserositis, familial hypercholesterolemia, hypothroidism, the Dyggve-Melchoir-Clausen syndrome, Sandhoff disease, and various genetic hematologic diseases. Genetic counseling and care to patients with genetic diseases is available in Beirut from the Faculty of Medicine at American University and St. Joseph University. Also, the Lebanese National Council for Scientific Research initiates and finances medical genetics programs.

Autosomal dominant secundum atrial septal defect with various cardiac and noncardiac defects: a new midline disorder.

We report on a Lebanese family in which 12 persons had an atrial septal defect and various cardiac and noncardiac anomalies. Cardiac anomalies are left axis deviation of QRS, right bundle branch block, atrial fibrillation, Wolff-Parkinson-White syndrome, nodal atrioventricular rhythm, aortic stenosis, pulmonic valve stenosis, mitral stenosis (Lutembacher syndrome), and low implantation of the tricuspid valve (Ebstein disease). Noncardiac abnormalities consisted specially of the presence of hypertelorism, cleft lip, and pectus excavatum. This combination appears to constitute a hitherto undescribed autosomal dominant midline disorder of the heart and upper half of the body with almost full penetrance and variable expressivity. The mutation does not map to any known locus involved in atrial septal defect or conduction block.

Two sibs with myoclonic epilepsy, congenital deafness, macular dystrophy, and psychiatric disorders.

We present a family with four children born to second-cousin parents. Two of the children had myoclonic epilepsy, congenital deafness, a dystrophic pattern of the macular pigment epithelium, incomplete right bundle branch block, and psychiatric disorders appearing after fever episodes. Results of all laboratory investigations including mitochondrial DNA analysis were normal. Despite the fact that this condition resembles one reported by Latham and Munro in 1937, it is possible that we might be reporting on a new autosomal recessive syndrome.

Chromosome 7q22-q31 duplication: report of a new case and review.

We report on a girl with psychomotor retardation, growth retardation, microcephaly, frontal bossing, large ears, small nose, high arched and narrow palate, short neck, and generalized hirsutism. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 7q22-->q31.3 duplication. Comparison with other reported cases shows some resemblance but insufficient to enable us to establish a definite syndrome with specific clinical manifestations. The importance in better analyzing further cases by new molecular cytogenetics techniques is raised.

HLA phenotype polymorphism in the Lebanese population.

The HLA-A, -B, -DR and DQ phenotypes have been defined in a panel of 217 Lebanese. These subjects were all unrelated, belonged to different religious communities and originated from the various provinces of Lebanon. All the broad class I specificities tested, except splits A25(10), B54(22) and B56(22), were present in this panel. When HLA-A and -B antigen frequencies were compared with data on the Caucasoids, Negroids and Orientals, several similarities in antigen frequencies could be found between some frequencies observed in the Lebanese and those observed in the Negroids and/or Orientals. There were no frequencies equivalent to those particular to the Caucasoids. In addition, two groups of class I antigens could be distinguished: a first group (A32, B14, B18, B35, B38, B39, B41 and B50) showing higher frequencies, and a second group (A31, B27, B60 and B62) showing lower frequencies than those observed in the Caucasoids, Negroids and Orientals. However, when analysed separately, several mediterranean ethnic groups, notably the Greeks and Italians, have a frequency profile equivalent to that of the Lebanese, with the exception of the B41 specificity, which is particularly high in the Lebanese (14.2%). The data concerning the class II antigens are the most interesting. All the specificities were present in the panel. The HLA-DR5 is the highest frequency of DR antigens in the present panel (58.9%) and nearly all DR5 positive individuals are DR11. The DR11 allele accounts for 33.1% of the total DR gene frequency. The highest DQ antigen frequency is that of DQ3 (76.4%), the majority of which is DQ7 (66.4%). We observed a high DR11-DQ7 haplotype frequency (29.4%) with a significant delta value for linkage disequilibrium. There is no linkage disequilibrium between B41 and DR11. The commonly observed linkage disequilibrium between the DQ5 allele, and the DR1, DR2, DR10 and DR14 alleles are not significant in this Lebanese panel.

Overlap between Baller-Gerold and Rothmund-Thomson syndrome.

We report a male patient with craniosysnostosis, bilateral radial and ulnar hypoplasia, absent thumbs, poikiloderma, and short stature. His parents are first cousins. Although this patient was originally diagnosed as having Baller-Gerold syndrome it is more likely that he has Rothmund-Thomson syndrome or a similar disorder. This report confirms the overlap between these two syndromes, and that Baller-Gerold syndrome is essentially a diagnosis of exclusion.

[Clinical and molecular genetics of familial bundle branch block related to chromosome 19]. / Génétique clinique et moléculaire d'un bloc de branche familial lié au chromosome 19.

Four large Lebanese families were observed for several years and over several generations which enabled the authors to describe the clinical electrocardiographic and prognostic features of a hereditary conduction defect and to locate the culprit gene at 19q 13.3. The ECG showed a healthy group and an affected group (mainly right bundle branch block, hemiblocks or complete AV block) and an undetermined group with minor QRS changes in the right precordial leads. The mode of transmission was autosomal dominant. The estimation of penetration in the observed pedigrees and in previously published pedigrees gave a value of 70% in men and 50% in women. There were, therefore, many healthy carriers of the mutation. The onset was congenital (8 babies aged 15 days to one year were affected). Healthy carriers followed up for 10 to 20 years remained normal. The clinical and ECG features progressed in 19% of subjects in the undetermined group. The changes progressed to complete AV block in 8% of affected subjects, both babies and adults. Several cases of sudden infant death were reported but were not documented. The detection of the culprit gene was made by genetic mapping. Markers situated at q 13.3 on chromosome 19 showed linkage. The haplotype related to the pathology was always present in the affected subjects. The genetic interval was 7 centiMorgans.

[Autosomal dominant Mendelian midline complex. Secundum atrial septal defect associated with cardiac and facial-thoracic defects. A familial case]. / Complexe mendélien de la ligne médiane. Communication interauriculaire de type ostium secundum associée à des malformations cardiaques et facio-thoraciques. A propos d'un cas familial.

The kindred of 38 individuals reported here have various anomalies: 1. facio-thoracic malformations: hypertelorism, nasal deviation, cleft lip and palate, upper-incisors diastema and pectus excavatum; 2. cardiac anomalies: sinus node bradycardia, atrial fibrillation, nodal rhythm, atrial septal defect. Wolff-Parkinson-White syndrome, low insertion of the septal tricuspid valve corresponding to an Ebstein syndrome, pulmonic "en dôme" valve stenosis, aortic valve stenosis, long QT, and intraventricular conduction blocks. Almost all these defects are septal or para-septal. Mitral stenosis is probably rheumatoid. Such median varied pathology has not been yet reported. All the extra-cardiac anomalies are situated along the vertical upper half-body midline. All cardiac anomalies are in the septal or para-septal region. It is an autosomal dominant trait that implies the early embryonic development of the midline of cardiac and extra-cardiac structures.

[Blood and leukocyte glutathione and glutathione S-transferase: relationship to cholesterolemia in healthy volunteers]. / Glutathion et glutathion S-transférase sanguins et leucocytaires: relation avec la cholestérolémie chez des volontaires sains.

Hypercholesterolemia increases the oxidation of low density lipoprotein (LDL) which subsequently leads to atherogenesis. The oxidized LDL are also known to increase in vitro macrophage synthesis of glutathione. The purpose of this study was to investigate the relationship between lipid parameters and the glutathione system (glutathione, glutathione S-transferase) in total blood and within leukocytes. The glutathione and glutathione S-transferase were evaluated by spectrophotometric methods in sixty-two healthy volunteers (32 women, 30 men, mean age 39.9 +/- 7.7). No correlation was found between the level of blood cholesterol and the values of the blood glutathione system. However, a positive correlation between the values of glutathione and glutathione S-transferase in leukocytes and the blood cholesterol level was only found in women (r = 0.55 and r = 0.50 respectively, p < 0.01). We also found in men a positive correlation between body mass index and glutathione S-transferase in total blood and within leukocytes (r = 0.38, p < 0.05, r = 0.5, p < 0.01 respectively). No correlation was found between age, smoking and the values of the glutathione system. Our results suggest that the glutathione system in leukocytes is related to blood cholesterol levels. The fact that this positive correlation was only observed in women points to a possible role of estrogens in the regulation of the glutathione system which merits to be further studied.