High Rate Of Consanguinity Research Articles

Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia

Autosomal recessive forms of Charcot-Marie-Tooth disease (CMT) account for less than 10% of all CMT cases, but are more frequent in the populations with a high rate of consanguinity. Roma (Gypsies) are a transnational minority with an estimated population of 10 to 14 million, in which a high degree of consanguineous marriages is a generally known fact. Similar to the other genetically isolated founder populations, the Roma harbour a number of unique or rare autosomal recessive disorders, caused by "private" founder mutations. There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G. We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance. We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM_006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM_033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively. The success of molecular genetic analysis in all families confirms that autosomal recessive forms of CMT caused by mutations on the NDRG1 and HK1 genes are common causes of inherited neuropathies among Slovak Roma. Providing genetic analysis of these genes for patients with Roma origin as a common part of diagnostic procedure would contribute to a better rate of diagnosed cases of demyelinating neuropathy in Slovakia and in other countries with a Roma minority.

Diagnostic challenges of aminoacidopathies and organic acidemias in a developing country: A twelve-year experience

BackgroundDiagnosis of aminoacidopathies and organic acidemias constitutes a real challenge in a developing country with high consanguinity rate and no systematic newborn screening. We report a twelve-year experience with the identification of these disorders in Lebanon, based on their clinical and biochemical profiles. MethodsIn this retrospective study, we reviewed clinical presentation and biochemical investigations of 294 patients. Traditional chromatographic methods were used for analyses. Findings were linked to the identified disorders. ResultsOut of 2921 patients, presenting to our metabolic program with neurological, digestive, family history and/or other symptoms suggestive of aminoacidopathy or organic acidemia, 294 patients were included with confirmed amino or organic acid disorder. The overall analytical yield was 10%. Aminoacidopathies were three-fold higher than organic acidemias. Phenylketonuria and methylmalonic acidemia were the most frequent. The majority of patients (79%) were symptomatic (median age: 14months, range: 1day–44years), mainly with neurological manifestations (87%). Intellectual disability was mostly due to phenylketonuria (73%). Chronic liver failure was frequent in maple syrup urine disease (53%). Plasma amino and urine organic acid chromatography were diagnostic in 8.8% and 3.9% of analyzed cases, respectively. Change in chromatographic technique from reversed-phase to ion-exchange enhanced the detection of many aminoacidopathies. ConclusionsIn the absence of newborn screening, the majority of aminoacidopathy and organic acidemia cases are still diagnosed clinically. This study emphasizes the importance of clinical awareness and accurate biochemical analyses as key tools for diagnosis in countries like ours, and the necessity for a comprehensive national newborn screening program.

Autism Spectrum Disorders and Inborn Errors of Metabolism: An Update

Autism spectrum disorder is characterized by social communicative deficits with restricted interests occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems, such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these conditions. A computer-assisted search was performed to identify the most common inborn errors of metabolism associated with autism. The following disorders were identified: phenylketonuria, glucose-6-phosphatase deficiency, propionic acidemia, adenosine deaminase deficiency, Smith-Lemli-Opitz syndrome and mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deficiency. The risk of autistic features is increased in children with inborn errors of metabolism, especially in the presence of cognitive and behavioral deficits. We propose that affected children should be screened for autism.

A Novel Mutation in FGD4/FRABIN Causes Charcot Marie Tooth Disease Type 4H in Patients from a Consanguineous Tunisian Family

Charcot-Marie-Tooth (CMT) disease constitutes a clinically and genetically heterogeneous group of hereditary neuropathies characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness, deformation of the feet, and loss of deep tendon reflexes. CMT4H is an autosomal recessive demyelinating subtype of CMT, due to mutations in FGD4/FRABIN, for which nine mutations are described to date. In this study, we describe three patients from a consanguineous Tunisian family, presenting with severe, early onset, slowly progressive, autosomal recessive demyelinating CMT, complicated by mild to severe kyphoscoliosis, consistent with CMT4H. In these patients, we report the identification of a novel homozygous frameshift mutation in FGD4: c.514_515insG; p.Ala172Glyfs*27. Our study reports the first mutation identified in FGD4 in Tunisian patients affected with CMT. It further confirms the important clinical heterogeneity observed in patients with mutations in FGD4 and the lack of phenotype/genotype correlations in CMT4H. Our results suggest that FGD4 should be screened in other early-onset CMT subtypes, regardless of the severity of the phenotype, and particularly in patients of consanguineous descent. In Tunisians, as in other populations with high consanguinity rates, screening of genes responsible for rare autosomal recessive CMT subtypes should be prioritized.

Pediatric allergy and immunology in Israel

After the geographic and sociodemographic settings as well as the health care in Israel are briefly described, the scope of pediatric allergy and immunology in Israel is presented. This includes specific disorders commonly encountered, the environment that induces symptoms, the specialists who treat them, and the common challenges of patients, parents, doctors, and allied health personnel who collaborate to manage the maladies and patient care. Allergies usually affect some overall 15-20% of the pediatric population. The main allergens are inhaled, ingested, or injected (insects stings). Generally, the incidence of the various allergens affecting children in Israel, is similar to other parts of the Western world. Owing to the high consanguinity rate in the Israeli population, the prevalence of the various immunodeficiency conditions (in the adaptive as well as the innate system) is higher than that reported worldwide. Pediatric allergists/immunologists also treat autoimmune disorders affecting the pediatric group. Pediatric allergy and clinical immunology are not separate specialties. The 25 specialists who treat children with allergic/immunologic diseases have undergone a basic training in Pediatrics. They also received an additional 2-yr training in allergy and clinical immunology and then have to pass the board examinations. They work mainly in pediatric allergy units, in several hospitals that are affiliated to the five medical schools in the country. Aside from clinical work, most of the centers are also heavily involved in clinical and basic research in allergy and immunology.

Septo-optic dysplasia complex: Clinical and radiological manifestations in Omani children

Background:Septo-optic dysplasia (SOD), also known as de-Morsier's syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia (ONH), pituitary gland hypoplasia, and midline abnormalities of the brain including absence of septum pellucidum and corpus callosum dysgenesis. It is typically diagnosed in infancy and has a variable presentation that includes visual, neurologic, and/or hypothalamic-pituitary endocrine deficits.Purpose:To demonstrate the ophthalmic, endocrine, and neurologic spectrum of SOD in five Omani children and address the crucial role of high-resolution neuroimaging for its early and accurate diagnosis.Materials and Methods:A retrospective chart review was performed in 2010 of all children in the pediatric ophthalmology database of Sultan Qaboos University Hospital (SQUH) who were diagnosed to have ONH. All relevantdemographic, ophthalmic, neurologic, endocrine, and neuro-radiological manifestations were recorded in a data collection form. All previous neuroimaging results were reviewed by a neuro-radiologist.Results:Five patients (four males, one female) with the diagnosis of ONH were included in the study. They presented during the period 1998-2008. All patients were born at term, with normal birth weights to healthy mothers with insignificant antenatal history. Age at presentation ranged from three months to one year. Manifestations at presentation included severe visual impairment (5/5), neonatal hypoglycemia (3/5), seizure disorder (2/5), and failure to thrive (4/5). ONH was bilateral in 3/5 patients and unilateral in (2/5). Brain and orbit imaging revealed varying anomalies in all patients. These included absent septum pellucidum (3/5), severe corpus callosum agenesis (1/5), ectopic pituitary (5/5), falx cerebri deficiency (1/5), optic nerve hypoplasia (5/5), optic chiasmal hypoplasia (5/5), and olfactory tract hypoplasia (1/5). Endocrine deficits were detected in 4/5 patients (3 with panhypopituitarism, and 1 with growth hormone deficiency) and necessitated replacement therapy.Conclusion:SOD is a clinically heterogeneous disorder with a wide spectrum of ophthalmic, endocrine, and neurologic manifestations. All features might not be present in a single patient. A high consanguinity rate and lack of history of alcohol and drug use were observed in our cohort. Most affected children present first to the pediatrician with failure to thrive. Radiological confirmation of ONH necessitates high-resolution imaging and interpretation by an experienced neuro-radiologist. In our cohort, all patients with ONH had associated optic chiasmal hypoplasia. Early detection and treatment reduces disease-related morbidity, and can be life saving.

620 The Pattern of Neural Tube Defects in a Highly Endogamous Society: 25 Year Incidence Trends

ObjectiveThe aim of this study is to determine the incidence and trends of NTD over a period of 25 years in the State of Qatar.DesignThis is a retrospective hospital based...

1038 Urea Cycle Defects- Misdiagnoses and Wrong Diagnoses

BackgroundUrea cycle defects (UCD) constitute a group of rare metabolic disorders that involve the enzymes of every step of urea cycle. Deficiency of one of these enzymes leads to hyperammonemia...

Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

BackgroundTunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities.MethodWe report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory.ResultsWe identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa.ConclusionThis report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for molecular diagnosis. Indeed, our report should help designing appropriate measures for carrier screening, better evaluation of diseases burden and setting up of preventive measures at the regional level.

Charcot Marie Tooth Disease - Autosomal Recessive Forms: Clinical, Electrophysiology and Genetic Study in a Tunisian Cohort (P05.149)

Objective: To investigate recessive forms in a Tunisian population with a high consanguinity rate. Background Charcot Marie Tooth disease (CMT) is the most frequent hereditary peripheral neuropathy. Autosomal Recessive forms of CMT are known to be the least common forms worldwise. Design/Methods: Among the prospective cohort on CMT of the Razi hospital - Tunisia, we included patients with recessive inheritance. All patients had clinical examination and were assessed by the Overall Neuropathy Limitations Scale (ONLS) and CMT neuropathy scale (CMTNS). ENMG study and genetic testing were also performed in all cases. Results: 33/70 patients belonging to 16 families were included, with a sex ratio of 0,6. Consanguinity was found in 94% of cases. Mean age of patient was 20,8 years. Mean age of onset was 3,7 years. Walking symptoms were observed in 56,7%. Amyotrophy was detected in 81,8 %. Weakness was found in 69,7% in upper limbs and in 87,9% in lower limbs. ONLS score was at 4,7 and CMT score at 12,2%. Axonal neuropathy was found in 48,5% and demyelinating (CMT4) in 51,5%. Axonal polyneuropathy was more frequently associated to early onset in 90.9% (p Conclusions: We presented a large serie of recessive forms of CMT. In fact, they represented 47% of all cases because of the high rate of consanguinity in our region. Comparatively with dominant forms, AR ones were caracterised by an earlier onset, more severe clinical features with important amyotrophy and handicap. Disclosure: Dr. Kacem has nothing to disclose. Dr. Gargouri has nothing to disclose. Dr. Ben Djebara has nothing to disclose. Dr. Hizem has nothing to disclose. Dr. Gouider has nothing to disclose. Dr. Leguern has nothing to disclose.

Abstract 2637: Application of identity-by-descent (IBD) approach to genetic mapping of susceptibility locus in hereditary esophageal squamous cell carcinoma (ESCC) by high density SNP array analysis

Abstract Background and aims: Esophageal cancer (EC) is a deadly disease with a very low 5-year survival rate. The incidence of EC shows great geographical variations with high prevalence in Northern China. Although epidemiological studies suggest that environmental factors may be etiologic factors of EC, strong evidence supporting a causative role of genetic factors in familial EC comes from i) familial aggregation of EC in Yangcheng County, ii) the distinct high EC incidence in Chaoshan migrants to Nanao, and iii) molecular genetic studies such as BRCA2 germline mutations. Recent technological advances allow the identification of long regions of homozygosity (known as IBD segments) in genomic DNAs, which represent the sharing of a common ancestor in those regions, using the high density SNP arrays. Previous studies suggest that a high rate of consanguinity, which produces germline genomic homozygosity, is associated with cancers. We aim to use the IBD approach for mapping the susceptibility locus with low-penetrance SNPs in hereditary ESCC patients in Henan, one of the highest ESCC risk regions in the world. Screening programs based on knowledge of founder mutations may reduce cancer mortality by prevention. Thus, our second aim is to assess if a founder effect exists and predisposes individuals to ESCC in Henan. Methods: Genomic DNAs were extracted from blood samples of Henan family history positive (FH+) ESCC patients and healthy normal individuals. The germline homozygosity in 30 Henan FH+ ESCC patients was explored by using Affymetrix GeneChip Human mapping SNP array (∼238K SNPs, Sty I). IBD analysis was performed using the PLink software. Results: There is longer IBD segment length associated with FH+ ESCC compared with control groups. The 27 IBD segments in FH+ ESCC samples having no overlap with control/Hapmap may encompass the potential cancer-susceptibility loci and should be further examined. However, no strong evidence for founder effect was observed by IBD approach for hereditary ESCC in Henan population. Conclusions: The increased length of germline genomic homozygosity association with hereditary ESCC in Henan is observed. Due to the small sample size in the current study, the association is considered hypothesis-generating only. The importance of these IBD segments to the etiology and development of ESCC in high risk areas require further study with an expanded sample size for validation. Acknowledgements: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China (HKU 3/06C to M.L.L.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2637. doi:1538-7445.AM2012-2637

Colorectal cancer risk is not associated with increased levels of homozygosity in Saudi Arabia

Purpose:Runs of homozygosity (ROHs) represent a measure of the extent of autozygosity and are correlated with the extent of inbreeding. Recently, it has been suggested that ROHs may contribute to the risk of colorectal cancer (CRC). The high rate of consanguinity and CRC in the Saudi population prompted us to test the role of autozygosity in the CRC risk.Methods:We compared 48 Saudi CRC patients to 100 ethnically matched controls, processed on the Affymetrix 250K StyI SNP GeneChip platform and analyzed using the plink package.Results:We could find no evidence of a significant relationship between autozygosity and CRC risk.Conclusion:The negative results in our study add additional significance to what has been previously reported in literature, as this is the first study to address these questions in an inbred population. Our subgroup analysis of patients with microsatellite unstable-positive tumors as compared with other groups did not significantly change our results. Although these results do not rule out the presence of recessively acting CRC-predisposing genes in a small percentage of patients, which our relatively small sample size could not capture, they suggest that such genes are unlikely to account for the disturbingly high incidence of CRC in our consanguineous population.Genet Med advance online publication 5 April 2012.

High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families

Recessive or co-dominant single-gene mutations disrupting leptin melanocortin pathway cause severe obesity and hyperphagia. Since Pakistan has a very high rate of consanguinity, therefore, a significantly higher incidence of monogenic obesity is expected in its population. We have assessed the incidence of LEP and MC4R mutations and associated hormonal profiles, in a cohort of randomly selected Pakistani children with early onset of severe obesity. Sixty two unrelated children of consanguineous parents, with a weight-for-age percentile >97 were recruited in the study. Screening for mutations in the coding regions of LEP and MC4R was performed by direct sequencing. Serum hormone concentrations were determined by immunoassay. LEP mutations were found in 16.1% of the probands. Of these, 9 probands carried the homozygous frameshift mutation, G133_VfsX14, whereas one patient had a homozygous mutation involving deletion of 3 base pairs, (I35del). In these probands, leptin levels were very low or undetectable and insulin levels were increased in 33%. Homozygous MC4R mutations, M161T and I316S, identified separately in 2 subjects (3.2%), were associated with severe obesity, hyperphagia, hyperleptinemia and hyperinsulinemia. The heterozygous M161T sibling had normal body weight and hormone levels and the parents were only mildly overweight. Based on genetic analysis of LEP and MC4R genes only, we elucidated genetic causality of severe obesity in 20% of our patients confirming high prevalence of monogenic form of obesity in this consanguineous population. Co-dominancy of MC4R is exacerbated in this group with non-penetrance of obesity in heterozygous loss-of-function MC4R mutation carriers. The sub-ethnic specificity of LEP mutation, G133_VfsX14, suggests a founder effect.

Clinical epidemiology of skeletal dysplasias in South America

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre-established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9-3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL-1) and according to international classification, 33% of cases fit into the G-25 (osteogenesis imperfecta), 29% in Group-1 (FGFR3), and 8% in Group-18 (Bent bones). The prevalence of the main OCD types were: OI-0.74 (0.61-0.89); thanatophoric dysplasia-0.47 (0.36-0.59); and achondroplasia-0.44 (0.33-0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate.

Genetic bases and phenotypes of autosomal recessive Parkinson disease in a Turkish population

To evaluate the phenotype and the frequencies of mutations in PRKN, DJ1 and PINK1 genes in patients with Parkinson disease (PD) in Turkey. Eighty-six patients from 77 PD families participated in the study. Seventy-four families were originating from Turkey, two families from Greece and one family from Bulgaria. All patients underwent detailed neurological examination. PRKN, PINK1 and DJ1 genes were sequenced, and dosage analysis was performed by multiplex ligation-dependent probe amplification. Sixteen patients with PD were found to carry homozygous (n = 14) or compound heterozygous (n = 2) PRKN mutations. We identified exon rearrangements, three point mutations and one new point mutation in exon 2 (p.K27del). In two families, two new PINK1 point mutations (L31X and P416L) were identified. No pathogenic mutations were found in DJ1 gene. Clinical phenotypes of PRKN patients were comparable to previously described features, but only in four of 13 families, the pedigree structure was clearly consistent with an autosomal recessive (AR) mode of inheritance in comparison with nine families where also different pattern of transmission could have been possible. Our data suggest that the PRKN gene mutation is the most frequent form of ARPD in Turkey. The proportion of mutations with regard to the age of onset in our population is in the range of those previously described, but our pedigrees are characterized by high rate of consanguinity, which might explain the high proportion of families with homozygous mutations and of patients in more than one generation. Pathogenic DJ1 mutations do not seem to play a major role in Turkey.

Newborn screening in the Middle East and North Africa – challenges and recommendations

Newborn screening in the Middle East and North Africa – challenges and recommendations

Molecular study of a consanguineous family with autosomal recessive mental retardation and speech disorder

A B S T R A C T Mental retardation (MR) is one of the most frequently found major genetic disorders around the world, affecting 1-3% of the people in the general population. The recent advancement in molecular biology and cytogenetic study has made possible the identification of new genes for a variety of genetic disorders including autosomal recessive MR. Recessive genetic disorders are common in Pakistan due to the high rate of consanguinity. A central focus of the present study was to map and identify the disease causing gene in a mentally retarded consanguineous Pakistani family with speech disorder. The study comprises of 20 individuals including 10 patients. Genetic analysis of autosomal recessive MR and speech disorders was carried out for eight known fundamental loci sorted out on the basis of clinical features. These loci including 3p26.2, 3p21.3, 7q22, 8p22, 11p15, 14q11.2-q12, 19p13.12, and 22p13 were screened using polymorphic microsatellite markers. To identify the disease locus, genomic DNA from each individual was genotyped for homozygosity analysis. Microsatellite markers were amplified using PCR. The study provided valuable data to exclude linkage of the above mentioned loci. The absence of any linkage of the Pakistani family with autosomal recessive MR to the eight well known loci, confirms the genetic heterogeneity of MR. These results need to be verified and the candidate gene be found by a complete genome scan, which may help us in establishing the genotype-phenotype correlation of MR, improving genetic counseling, carrier screening, DNA based prenatal diagnosis and the opportunity to develop appropri ate animal models to test new forms of cell or gene therapies.

Two novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11β hydroxylase deficiency in a Tunisian family

Steroid 11β hydroxylase deficiency (11β-OHD) (OMIM # 202010) is the second most common form of congenital adrenal hyperplasia (CAH), accounting for 5–8% of all cases. It is an autosomal recessive enzyme defect impairing the biosynthesis of cortisol. The CYP11B1 gene encoding this enzyme is located on chromosome 8q22, approximately 40 kb from the highly homologous CYP11B2 gene encoding for the aldosterone synthase. Virilization and hypertension are the main clinical characteristics of this disease. In Tunisia, the incidence of 11β-OHD appears higher due to a high rate of consanguinity (17.5% of congenital adrenal hyperplasia). The identical presentation of genital ambiguity (females) and pseudo-precocious puberty (males) can lead to misdiagnosis with 21 hydroxylase deficiency. The clinical hallmark of 11β hydroxylase deficiency is variable, and biochemical identification of elevated precursor metabolites is not usually available. In order to clarify the underlying mechanism causing 11β-OHD, we performed the molecular genetic analysis of the CYP11B1 gene in a female patient diagnosed as classical 11β-OHD. The nucleotide sequence of the patient’s CYP11B1 revealed two novel mutations in exon 4: a missense mutation that converts codon AGT (serine) to ATT (isoleucine) (c.650G>T; p.S217I) combined with an insertion of a thymine at the c.652–653 position (c.652_653insT). This insertion leads to a reading frame shift, multiple incorrect codons, and a premature stop in codon 258, that drastically affects normal protein function leading to a severe phenotype with ambiguous genitalia of congenital adrenal hyperplasia due to 11β hydroxylase deficiency.

Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity

Xeroderma pigmentosum (XP) is a rare disorder characterized by a high skin sun-sensitivity predisposing to skin cancers at an early age. Among Tunisian XP patients with an intermediate skin phenotype, 92% presented neurological abnormalities related to XPA gene deficiency. Clinical variability of the XP-A phenotype is associated with a mutational heterogeneity. In the present study, two Tunisian families with severe dermatological and neurological XP phenotypes were investigated in order to determine clinical characteristics and genetic basis. Two Tunisian families with four XP affected children were examined in the Dermatology Department. Clinical features showed severe presentation of the disease. Coding regions of the XPA gene were analysed by direct sequencing. Results showed the presence of a novel mutation, p.E111X, in three patients belonging to the same family and presenting a very severe phenotype i.e. development of skin lesions and neurological signs before 1 year age. For the other patient, we identified a nonsense mutation, p.R207X, already identified in a Palestinian XP-A patient. Identification of novel causing mutations in Tunisian XP-A patients shows the genetic and mutational heterogeneity of the disease in Tunisia. Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity.

Thirty years of primary immunodeficiencies in Turkey

Turkey, with its population of some 75 million, has a high rate of consanguineous marriages. Because the majority of the primary immunodeficiencies (PIDs) are inherited as autosomal recessive (AR) forms, the high consanguinity rate leads to a high prevalence of PID diseases in Turkey. The first pediatric immunology division was established in 1972, since then over 10 other immunology divisions have been established in different cities. Approximately 4,000 patients with possible PID are referred to these centers annually. The percentages of some of the major immunodeficiency groups and individual disease numbers among these patients differ somewhat in comparison with Western countries, likely because the relative incidences of PIDs with AR inheritance and of rare diseases are higher. These characteristics of the patient population, and our determination of differences in disease presentation and unusual features, have led us to undertake studies in collaboration with various centers in Western countries. These collaborations have contributed to the identification of the genes responsible for some rare immunodeficiencies, to the resolution of the genetic heterogeneity underlying conventional phenotypes, and to the description of new clinical phenotypes.