Omani Family Research Articles

A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion

BackgroundDysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes.MethodsSNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used.ResultsWe identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function.ConclusionsWe have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.

Mutations in C4orf26, Encoding a Peptide with In Vitro Hydroxyapatite Crystal Nucleation and Growth Activity, Cause Amelogenesis Imperfecta

Autozygosity mapping and clonal sequencing of an Omani family identified mutations in the uncharacterized gene, C4orf26, as a cause of recessive hypomineralized amelogenesis imperfecta (AI), a disease in which the formation of tooth enamel fails. Screening of a panel of 57 autosomal-recessive AI-affected families identified eight further families with loss-of-function mutations in C4orf26. C4orf26 encodes a putative extracellular matrix acidic phosphoprotein expressed in the enamel organ. A mineral nucleation assay showed that the protein's phosphorylated C terminus has the capacity to promote nucleation of hydroxyapatite, suggesting a possible function in enamel mineralization during amelogenesis.

Coexistence of sickle cell disease and severe congenital neutropenia: first impressions can be deceiving

We report an Omani family in whom the propositus had a rare coexistence of sickle cell disease and severe congenital neutropenia associated with a mutation in ELANE. In contrast to his siblings with sickle cell disease, the severity of HbSS-associated complications such as painful crises and acute chest syndrome was significantly reduced. His course of the disease had markedly worsened after initiating G-CSF therapy. These clinical observations suggest that neutropenia may ameliorate inflammatory responses and thus display a modulating factor with respect to the clinical course of sickle cell disease.

The β-globin promoter −71 C>T mutation is a β+ thalassemic allele

A novel β-globin gene promoter (-71 C>T) nucleotide change was recently posted to the HbVar database (ID 2701) without precision on phenotype and ethnicity. We found the same change in compound heterozygosity with Hb S [β6(A3)Glu>Val] in an Omani family with almost equal expression of Hb A and Hb S. This suggested that the -71 C to T mutation may be a mild β-thalassemic allele. Subsequent search found three other independent cases with the same atypical Hb A:Hb S ratio, further confirming the mild thalassemic feature of this mutation. In addition, molecular screening of a set of subjects (with only Hb A) with borderline Hb A(2) or MCV values revealed the presence of -71 C>T change in heterozygous state, altogether assigning the mutation as a mild β(+) thalassemic allele. In a region such as Oman, where several genetic conditions of the red blood cell coexist (α- and β-thalassemia, Hb S, Hb D, Hb E) in significant frequencies, it is crucial to decipher the molecular basis of these atypical forms of β(+) thalassemias, especially in a genetic counseling setting.

Severity ranking of non-deletional alpha thalassemic alleles: insights from an Omani family study

In an Omani family, four different alpha thalassemic alleles, one single-gene deletional (-α(3.7) ) and three non-deletional forms (α(TSaudi) , α(Δ5nt) , and α(ΔG) ), interact in various combinations and result in two distinct hematological phenotypes, with and without HbH inclusions. After excluding the presence of potential genetic modifiers, viz associated β-thalassemic alleles or functional alpha hemoglobin stabilizing protein (AHSP) polymorphisms, we observed that only the genetic combinations involving α(TSaudi) mutation are associated with HbH inclusions (a marker of degree of α/β-chain imbalance) and high reticulocyte count (a marker of ongoing hemolysis). Overall, the α(TSaudi) mutation is associated with a more severe α-globin deficiency than the other two (α(Δ5nt) and α(ΔG) ) non-deletional α(0) thalassemic mutations. The likely molecular explanation is that the compensatory increase in the linked α1 globin gene expression is much more compromised in cases with α(TSaudi) mutation.

Identification of a Novel Frame Shift Mutation of the LDL Receptor Gene Causing Familial Hypercholesterolemia in Omani Family*

Synopsis: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused commonly by mutation in the low-density lipoprotein receptor (LDLR) gene. It is characterized by a high concentration of low-density lipoprotein cholesterol (LDL-C), and premature coronary artery disease. Purpose: In this study, we report a novel frame shift deletion mutation of the LDL receptor gene in Omani family. Methods: Five patients from the family were screened for mutations in the LDLR gene using direct sequencing of the promoter and 18 exons. Results: The probandwas a 10-year-old girlwith total cholesterol of 23.2mmol/L, LDL-C of 22.1mmol/L, triglyceride 0.8 mmol/L, HDL-C0.74mmol/L, ApoB4.5 g/L, Lpa 1110mg/L with tendon xanthomas and measured carotid intima media thickness (CIMT) of 1.05 mm. Both the parents and the other two sisters’ ages (13 and 15 years) had high LDL-C 7.1, 6.4, 5.2, and 6.4 mmol/L, respectively. The direct sequencing of the LDL-receptor gene revealed a homozygous frame shift deletion (272delG) of exon 3 in the proband. The parents and the two sisters were heterozygous for this variant. Conclusions: This study identified a novel framshift deletion mutation (272delG) in exon 3 of the LDL receptor gene that causes FH in this Omani family. In Oman the prevalence of FH is not known; therefore, more genetic studies are needed to characterize the molecular basis of FH.

A Qualitative Study on the Attitudes and Beliefs towards Help Seeking for Emotional Distress in Omani Women and Omani General Practitioners: Implications for Post-Graduate Training

This study aims to explore the attitudes and beliefs of Omani women attending primary health care and Omani general practitioners regarding help seeking behaviour for emotional distress. The study also intends to clarify the understanding of help seeking from both lay and professional perspectives in the context of Omani culture exploring factors related to doctors' training and health care services. A qualitative phenomenological study using semi-structured interviews was conducted at the Family Medicine Health Care Centre at Sultan Qaboos University Hospital. 20 lay informants (Omani women) and 10 professional informants (Omani family physicians) were interviewed. Two main sets of themes are presented in this study; 1). the original themes, which are presented in the results section and represent the descriptive level of analysis, and 2). the emergent themes are presented in the discussion section and represent the interpretive level of analysis. The original themes are: a) self help, with subthemes including the role of faith, talking and distraction. b) Health care and doctors, with subthemes including: reasons for seeing a doctor, reasons for not seeing a doctor, continuity of care, doctor-patient relationship and time. c) Traditional (folk) medicine. The emergent themes are: a) Talking b) Religious faith c) Cultural beliefs and d) The doctor's role. Cultural and religious beliefs were found to shape the experience of help seeking in the study group. In addition, factors associated with doctor-patient relationship were found to play a major role in determining the help seeking behaviour of women experiencing symptoms related to psychological distress. Professional informants emphasized the role of their training, availability of supporting services, time and continuity of care. The study showed discrepancy between lay and professional informants' beliefs regarding the role of family physicians in managing mental problems. This study recommends paying more attention to factors related to cultural beliefs, doctor-patient relationship and family physicians' role when planning health services and residency programs, and when planning research on aspects related to mental health in non-Western cultures.

Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of inherited neurodegenerative disorders in which the cardinal pathological feature is upper motor neurone degeneration leading to progressive spasticity and weakness of the lower limbs. Using samples from a large Omani family we recently mapped a gene for a novel autosomal recessive form of HSP (SPG35) in which the spastic paraplegia was associated with intellectual disability and seizures. Magnetic resonance imaging of the brain of SPG35 patients showed white matter abnormalities suggestive of a leukodystrophy. Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del). Measurement of enzyme activity in vitro revealed significantly reduced enzymatic function of FA2H associated with these mutations. These results demonstrate that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated HSP and radiological features of leukodystrophy. (c) 2010 Wiley-Liss, Inc.

Paramyotonia Congenita in 22 Members of an Arab (Omani) Kindred

Paramyotonia congenita in 22 members of Arab (Omani) family is reported. Four generations were affected. All had early onset around 1 year of age, with myotonia and cold intolerance. Age of onset in the index case was at 3 months of age. Six members with the disease were examined and investigated. To our knowledge, this is the first report of the condition from this region. Childhood presentation and differential diagnosis is discussed.

A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous neurodegenerative disorders in which the cardinal pathologic feature is upper motor neuron degeneration leading to progressive spasticity and weakness of the lower limbs. To date, 14 autosomal recessive HSP loci have been mapped. We have identified a large consanguineous Omani family in which an autosomal recessive form of HSP is segregating. The age at onset varied from 6 to 11 years and the course of the disease is progressive with intellectual disability and is associated with seizures in two individuals. To map the chromosomal location of the causative gene we undertook 250K gene chip SNP analyses of all affected individuals assuming that a founder mutation was responsible. All affected individuals shared a 20.4 Mb (3.25 cM) region of homozygosity located on chromosome 16q21-q23.1, defined by SNP markers rs149428 and rs9929635 (peak multipoint lod score of 4.86). Two candidate genes, dynein, cytoplasmic 1, light intermediate chain 2 (DYNC1LI2) and vacuolar protein sorting 4 homolog A (VPS4A), were sequenced but no disease causing mutations were identified. We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.

The Omani Family

To gain a better understanding of the Omani family, the paper first presents an overview of significant attributes that characterize Omani society and its people which include: the foundation of the Omani state, the strong influence of Arabic and Islamic heritage, the influences of tribalism, the emergence of modern Oman, and the challenges that confront the Omani family today. Through analysis of field research and relevant literature on measures of cohesiveness, the authors establish that the Omani family can be considered to be highly cohesive. As well, they assert their confidence that the power of the Islamic and Arabic traditions and heritage will continue to support and sustain the Omani family, thus enabling it to confront both current and future challenges.

Polysyndactyly, complex heart malformations cardiopathy, and hepatic ductal plate anomalies: an autosomal recessive syndrome diagnosed antenatally.

A distinct syndrome was ascertained in a 3-year-old girl and her brother. The proband was the first child of first cousin parents. She was born after an uneventful pregnancy. At birth, multiple congenital anomalies were noted: ptosis of the left eyelid, hypertelorism, anteverted nares, large fontanel, long philtrum, ungueal hypoplasia, polysyndactyly, single transverse crease, complex cardiopathy, and hepatic cysts. During another pregnancy of the mother, fetal ultrasonographic examination showed an hypertrophy of the right ventricle and atria, a dextroposition of the aorta, a bilateral renal pelvis dilatation, and a club foot. After termination of the pregnancy, necropsy showed facial anomalies, a small penis, a polysyndactyly, a ventricular septum defect, and a malformation of the ductal plate. Bonneau et al. [1983: J Genet Hum 2:93-105] described a family in which three sibs had a complex cardiac malformation, hexadactyly of the first toe, and syndactyly of the third and fourth fingers. Rajab [1997: Clin Dysmorphol 6:85-88] described two sibs with similar features in an Omani family. The sibs described in this report had anomalies of the ductal plate which were not reported in the two other families. These new findings are in favor of autosomal inheritance of this condition which is amenable to antenatal diagnosis.

Impaired prothrombinase activity of factor X Gly381Asp results in severe familial CRM+ FX deficiency

We investigated three members of a large Omani family affected by severe factor X (FX) deficiency (coagulant activity <1%) and showing marked differences in the onset of severe hemorrhagic symptoms. All patients were homozygous for a novel FX mutation (Gly381Asp) in the structurally conserved region of the serine protease active site. Expression levels of recombinant 381D-FX were similar to those of wt-FX, indicating the presence of a severe CRM+ FX deficiency, a poorly investigated condition. The 381D-FX was normally activated and did not show a detectable amidolytic activity. Instead, we observed a residual activity in a prothrombin-time based assay (1%) and in prothrombinase assays both in plasma (1%) and in purified systems (3%). Comparison with FX variants characterized by reduced activation suggests that mutations affecting FX activity might result in a more pronounced impairment of coagulation and thus in severe hemorrhagic phenotype. In addition, this study indicates that the hemorrhagic heterogeneity observed in FX deficiencies is only partially explained by molecular analysis of FX gene.

Localisation of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facies to chromosome 15q26

BACKGROUNDWe have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part...

Setleis syndrome

Setleis syndrome is a rare skin disorder characterized by congenital scar-like depressions on the temples and distinctive facial appearance. We report on two cases from a consanguineous Omani family, with typical features of this syndrome. The mother in one case has mild dysmorphic features reminiscent of this syndrome and the father of the other case has bitemporal scars only.