RESUMEN
Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutation-negative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition.
Asunto(s)
Pruebas Genéticas/métodos , Genoma Humano/genética , Mapeo Cromosómico/métodos , Consanguinidad , Exoma/genética , Familia , Femenino , Genes Recesivos/genética , Humanos , Italia , Masculino , Medio Oriente , Mutación/genética , LinajeRESUMEN
BACKGROUND: Hereditary hearing loss is a heterogeneous group of complex disorders with an overall incidence of one in every 500 newborns presented as syndromic and non-syndromic forms. Cadherin-related 23 (CDH23) is one of the listed deafness causative genes. It is found to be expressed in the stereocilia of hair cells and in the retina photoreceptor cells. Defective CDH23 have been associated mostly with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic (USH1D) or non-syndromic SNHL (DFNB12) deafness. The purpose of this study was to identify causative mutations in an Omani family diagnosed with severe-profound sensorineural hearing loss by whole exome sequencing technique and analyzing the detected variant in silico for pathogenicity using several in silico mutation prediction software. RESULTS: A novel homozygous missense variant, c.A7436C (p. D2479A), in exon 53 of CDH23 was detected in the family while the control samples were all negative for the detected variant. In silico mutation prediction analysis showed the novel substituted D2479A to be deleterious and protein destabilizing mutation at a conserved site on CDH23 protein. CONCLUSION: In silico mutation prediction analysis might be used as a useful molecular diagnostic tool benefiting both genetic counseling and mutation verification. The aspartic acid 2479 alanine missense substitution might be the main disease-causing mutation that damages CDH23 function and could be used as a genetic hearing loss marker for this particular Omani family.
RESUMEN
Hyperekplexia is characterized by neonatal hypertonia and exaggerated startle reflex in response to loud noise or tactile stimuli. Mutations in patients with hyperekplexia were evident in several genes encoding proteins involved in glycinergic neurotransmission, i.e., glycine receptor α and ß subunits, collybistin, gephyrin, and glycine transporter 2. We clinically and genetically characterized two large, unrelated consanguineous families with hyperekplexia. Affected members of the two families manifested hyperekplexia with mild mental retardation. Patients exhibited a novel homozygote c.593G>C missense mutation in GLRA1, resulting in amino acid substitution p.W170S in the corresponding mature glycine receptor α1 subunit. This mutation was absent in 400 randomly selected chromosomes in the same population. In conclusion, a novel p.W170S mutation in the extracellular ligand binding domain of glycine receptor α1 subunit was detected in patients with hyperekplexia and mild mental retardation.
Asunto(s)
Discapacidad Intelectual/genética , Hipertonía Muscular/genética , Receptores de Glicina/genética , Reflejo Anormal/genética , Reflejo de Sobresalto/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Mutación Missense , Omán , LinajeRESUMEN
Apolipoprotein E (APOE) polymorphism is a predictor of interindividual variability in plasma levels of lipids and lipoproteins and a predictor of risk of coronary artery disease (CAD). We studied the relationship between APOE polymorphism and lipid profiles and risk of CAD in Omani dyslipidemic patients. This retrospective study included 244 dyslipidemic patients, of whom 67 had CAD. Fasting blood glucose, lipids, and plasma lipoprotein levels were measured using standard methods, and APOE genotypes were detected by PCR-RFLP. The dyslipidemic patients had the following APOE allele frequencies: APOE*2, 0.030; APOE*3, 0.894; and APOE*4, 0.076. APOE allele frequencies between patients with and without CAD showed no significant differences. Compared to APOE*3/*3 homozygotes, APOE*4 allele patients had higher mean levels of low-density lipoprotein (LDL) cholesterol (p = 0.014), apoB (p = 0.031), lower mean levels of apoA1 (p = 0.043), and a trend of higher mean level of total cholesterol (p = 0.084). Thirty-one percent of patients with CAD had the APOE*4 allele compared to 26% with the APOE*3 allele, but this difference was not significant. Compared with APOE*3/*3 homozygotes, patients with the APOE*4 allele had 1.3 times higher risk for CAD after ignoring dyslipidemia, but this risk was modified after adjusting for dyslipidemia. In conclusion, among dyslipidemic patients, carriers of APOE*4 compared to homozygous carriers of APOE*3 had significantly higher levels of LDL cholesterol and apoB, but no relationship with CAD was found.
Asunto(s)
Apolipoproteína E3/genética , Apolipoproteína E4/genética , Dislipidemias/genética , Polimorfismo Genético , Adulto , Anciano , Apolipoproteína E2/genética , Enfermedad Coronaria/genética , Dislipidemias/complicaciones , Femenino , Frecuencia de los Genes , Genética de Población/métodos , Homocigoto , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Omán , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Estudios RetrospectivosRESUMEN
OBJECTIVE: To estimate the apolipoprotein E (apo E) allele distribution in the Omani population and to compare them with those of other populations. SUBJECTS AND METHODS: One hundred and sixty-two healthy Omanis of Arab Bedouin origin were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism. RESULTS: The apo E allele frequencies were: epsilon2, 0.052; epsilon3, 0.886; epsilon4, 0.062. This pattern of distribution, characterized by the lowest epsilon4 and among the highest epsilon3 allele frequencies in the world, was very similar to that of Arabs, Southern Europeans of the Mediterranean basin, Indians, and Japanese populations. CONCLUSION: The results indicate that the allelic distribution of apo E in healthy Omanis is characterized by low Apo epsilon4 and high epsilon3 allele frequencies similar to those of other Arab, Southern European, Japanese and Indian populations. The homogeneous distribution of apo E alleles in this group of populations might have been influenced by diet and/or genetic admixture.
Asunto(s)
Alelos , Apolipoproteínas E/genética , Genética de Población , Adolescente , Adulto , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Hiperlipidemias/genética , Masculino , Omán , Polimorfismo GenéticoRESUMEN
The relative frequencies of the *A allele of the APOA1 gene at -75 bp (M1-) and the C or T +83/+ 84 bp allele (M2-) varied significantly between populations. We found the frequencies of M1- and M2- to be 0.22 and 0.067, respectively, in 150 healthy Omanis. These frequencies were compared to frequencies found in other world populations.
Asunto(s)
Apolipoproteína A-I/genética , Polimorfismo Genético , Adolescente , Adulto , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Variación Genética , Humanos , Masculino , Omán , Reacción en Cadena de la PolimerasaRESUMEN
Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo-distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage-derived morphogenetic protein-1 (CDMP-1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP-1 biologically active carboxy-terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.