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leukoencephalopathy

Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report

Ashraf Yahia1,9,12, Liena Elsayed1*, Arwa Babai2, Mustafa A. Salih3, Sarah Misbah El-Sadig4,8, Mutaz Amin1, Mahmoud Koko5, Rayan Abubakr2, Razaz Idris2, Shaimaa Omer M.A. Taha6, Salah A. Elmalik13, Alexis Brice11,12, Ammar Eltahir Ahmed7,8, Giovanni Stevanin10,12

1Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan.

2Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.

3Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4Department of Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
5Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany.

6Department of Radiology, Dar Al Elaj specialized hospital, Khartoum, Sudan.
7Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
8Department of Neurology, Soba University Hospital, Khartoum, Sudan.

9Department of Biochemistry, Faculty of Medicine, National University, Sudan.

10Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France.
11APHP Pitié-Salpêtrière Hospital, Department of genetics, Paris, France.

12Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne

Universités UMR_S1127.

13Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

* Corresponding author

Abstract

Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM # 611105) is a genetic disease of the central nervous system characterized by lower limbs spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in DARS2 gene but has never been reported in Sub-Saharan Africa so far.

Case presentation: Two siblings, currently aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of a proband patient identified two compound heterozygous variants (NM_018122.4:c.1762C>G and c.563G>A) in DARS2 gene. Sanger sequencing confirmed the segregation of these variants in trans in both patients and further identified one asymptomatic patient (aged 20 years) who showed only brisk reflexes and mild lower limb spasticity. In contradistinction to the subtle clinical presentation, the latter had an abnormal MRI features and serum lactate levels comparable to her symptomatic siblings.     

Conclusion: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. Screening relatives of LBSL patients can detect asymptomatic cases and might have implications for counseling.

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Frequency of Selected Multiple Sclerosis Modifier Variants

 

 

Frequency of Selected Multiple Sclerosis Modifier Variants in a Healthy Sudanese Population

Authors name : Ola Almubarak Omer , Mohamed O Esiddeig , Muntaser Eltyeb Ibrahim

Affiliation : institute of endemic disease  university of Khartoum , Khartoum , sudan

Background : multiple sclerosis [MS] is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interaction.

Objective :   reviewing literature to filter MS modifier variants which is most likely associated with MS in Sudanese population according to its replication in African Americans , calculate the frequency of this variants in healthy Sudanese population and to compare this frequencies with the frequencies of this variants in other  populations.

Methods : A total of 29 single nucleotide polymorohisms [SNPs] were filtered , of which  28 SNP minor technology .  MAF of the  29th SNP was calculated in a 45 healthy Sudanese sample genotyped using whole exome sequencing. Both data sets are already available .Those calculated MAFs compared with MAF in the other populations .

 Results : Out of first  28 SNPs,  25 SNPs found to be represented in the SNP-array  .Out of those 25 SNPs , 12 showed significant differences between Sudanese and Europeans , 10 between Sudanese and East Asians , 8 between Sudanese and Americans, 4 between Sudanese and Africans. The  MAF of the 29th SNP rs10735781(EV15) in sudanese shows significant difference  in relation to other populations .

Conclusion : There is no statically significant difference between MAF of most of  MS modifier variants in Sudanese in relation to the other populations and the degree of difference are explained by ancestral relationship between populations differences in disease incidence between populations and finally differences in disease pathogenesis between different populations. In future MS association studies in Sudanese , it will be helpful and more affordable to use our filtered genes as candidate genes and  we recommend to test the association of more EBV related sequences (eg EBNA) than only  rs10735781(EV15).

 

                                                                                                                           

Key words: MS, SNP, variants, MAF.

 

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Novel variants causing inherited leukodystrophies

Novel variants causing inherited leukodystrophies in Sudanese families

Mutaz Amin1, Imen Dorboz2, Inaam N. Mohammed1, Ahlam A. A. Hamed1, Maha A. Elseed1, Ashraf Yahia1, Arwa Babai1, Eman Badi1, Melka O. EL-Amin1, Esraa Emad1, Simon Samaan2,3, Liena E. O. Elsayed1, Ammar E. Ahmed1* and Odile Boespflug-Tanguy2,4*

*Correspondence: Professor Ammar E. Ahmed: Faculty of Medicine, University of Khartoum, Qasr Street,11111 Khartoum, Sudan and Professor Odile Boespflug-Tanguy: INSERM 1141 Neuropediatrics and metabolic disorders unit, Hospital Robert Debre, Paris, France

Email: atahmed10@gmail.com  and odile.boespflug-tanguy@aphp.fr

1Faculty of Medicine, University of Khartoum, Sudan

2INSERM UMR 1141 PROTECT,  Université Paris Diderot- Sorbonne Paris Cité, France 

3Medical Genetic Department, Molecular Genetic unit, CHU APHP , Robert-Debré  Paris, France 

4Neuropediatrics and Metabolic Disorders Department, reference center for leukodystrophies and rare leukoencéphalopathies (LEUKOFRANCE), CHU APHP Robert-Debré, Paris, France

Abstract

Background: Leukodystrophies are a group of inherited disorders primarily affecting the white matter of the CNS. There are currently 30 recognized forms of leukodystrophies with distinct clinical, biochemical and radiological characteristics. However, the genetics of these classical forms of leukodystrophies remain unknown in many parts of the world especially in Sub-Saharan Africa.

Methods: In this study, we selected 5 consanguineous leukodystrophic families from Sudan using clinical and MRI recognition pattern. Genomic DNA was extracted and screened for mutations using NGS panel testing 153 leukodystrophies and leucoencephalopathies causing genes (NextSeq500 Illumina).

Results: Three novel homozygous variants were discovered: one (c.380G>C, p.Arg127Pro) in PSAP gene causing MLD, and two (c.831_838DUPATATCTGT, p.Ser280Tyrfs*8 and c.971T>G, p.Ile324Ser) in MLC1 gene in the two families with MLC. The segregation pattern was consistent with autosomal recessive inheritance. The pathogenicity of these variants was predicted using bioinformatics tools.

Conclusion: This is the first study to underlie the genetics of leukodystrophies in Sudan. Analysis of additional families are in progress in order to establish the whole spectrum of genetic variations causing inherited leukodystrophies in Sudanese families.

 

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Overlap of polymicrogyria, hydrocephalus, and Joubert Syndrome

Overlap of polymicrogyria, hydrocephalus, and Joubert Syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556

Edmund S. Cauley MPhil1,10, Ahlam Hamed MD2,10, Inaam N. Mohammed MD2, Maha Elseed MD2, Samantha Martinez1, Ashraf Yahia MSc3,4,5, Fatima Abuzar3, Rayan Abubakr MSc6, Mahmoud Koko MSc7, Liena Elsayed PhD3, Xianhua Piao MD8, Mustafa A. Salih MD9, M. Chiara Manzini PhD1*

1 Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington DC

2 Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

3 Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

4 Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan

5 Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités UMR_S1127

6 Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan

7 Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany

8 Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA

9 Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

10 these authors contributed equally to the study

 

Abstract (126 words)

Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malfromation including bilateral polymicrogyria, hydrocephalus, white matter defects, cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert Syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.

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Hyperprolinemia in schizophrenia:

Hyperprolinemia in schizophrenia: Underlying cause or potential result

Azaa Elshafi Khadir-MBBS. Msc. University of Khartoum, Sudan

Mohamed Abdalhameed Alnor- MBBS. Msc. MD. University of Khartoum, Sudan

Muntaser El Tayeb Ibrahim, B.Sc. M.Sc. Ph.D. University of Khartoum, Sudan

 

Introduction

Metabolic defects related to Schizophrenia are explained either by the unhealthy life style of schizophrenic patients including poor diet and sedentary behavior or the use of antipsychotic drugs that may contribute to metabolic disorders including obesity, diabetes mellitus, and cardiovascular disease. However genes and metabolites related to energy metabolism that may be altered in schizophrenia, appear to have changed rapidly during recent human evolution, probably as a result of positive selection. Some metabolic conditions and enzymatic deficiencies may in fact contribute to the pathogenesis of the disease including Proline dehydrogenase (PRODH).

Hereditary hyperprolinemia: type I abnormality in the proline oxidizing enzyme and type II caused by a deficiency of Δ-1-pyrroline-5-carboxylate dehydrogenase (P5CDh). The underlying mechanism regarding these two types may affect neurotransmitters (GABA), also stress conditions generate ROS which can mediate apoptosis.

 

Methods

 A family with tow sibling affected with schizophrenia and on antipsychotic treatment and three other siblings with learning disability and one healthy control were sampled. Whole Exome sequencing was carried out for the tow patients and one healthy control.

 

Results, Discussions and Conclusion

Of the 31deleterious mutations with high impact and associated with schizophrenia identified through the pipeline one mutation  in PRODH was of interest, as mutations in this gene was associated with both hereditary hyperprolinemia and schizophrenia. In investigating the genetic of schizophrenia a major question arises; Is the disease a secondary psychiatric manifestation following a course of metabolic disorder (syndromes) or is the underlying causes of schizophrenia that explain its pathophysiology  mainly a defect in metabolism? This could be answered by further understanding the action of PRODH, it`s genetic and protein interaction, related signaling pathways and epigenetic changes. Further testing to confirm the presence of high Proline or its metabolites in blood of a wider sample is recommended.

 

 

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Hereditary spinocerebellar degeneration in Sudan

 

Hereditary spinocerebellar degeneration in Sudan: maximizing the diagnostic yield through data revisiting

Ashraf Y. O. Mohamed1,4,5, Inaam N. Mohammed1, Ahlam A. A. Hamed1, Maha A. Elseed1, Mahmoud E. Koko2, Rayan A. Siddig1,  Mustafa A. Salih, Alexis Brice4,6,  Liena E. O. Elsayed1*, Ammar E. Ahmed1*, and Giovanni Stevanin4,5,6.

*Correspondence: Professor Ammar E. Ahmed and Dr.Liena Elbaghir Omer Elsayed, Faculty of Medicine , University of Khartoum, Qasr Street,11111 Khartoum, Sudan.

Email: atahmed10@gmail.com and liena.elsayed@gmail.com

1Faculty of Medicine, University of Khartoum, Khartoum, Sudan.

2Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany

3Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

4Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, 75013 Paris, France.

5Ecole Pratique des Hautes Etudes, EPHE, PSL université, 75013 Paris, France.

6APHP Pitié-Salpêtrière Hospital, Department of genetics, 75013 Paris, France.

 

 

Background: The post human genome project era has been characterized by a spurt of biological information shifting the quest towards making sense out of biological data rather than data generation.  Hereditary degenerative spinocerebellar disorders (SCD) are of the most common inherited (monogenic) neurological diseases with a wide range of genotypic and phenotypic characteristics. In a previous study, we succeeded in identifying new genes, new mutations and novel SCD genotype phenotype correlations using whole exome sequencing (WES) with an overall success rate of 50% (seven out of 14 families).

Methods: Reanalysis of next generation sequencing data on seven Sudanese families with SCD. In a previous study no genetic diagnosis had been reached in these families. Reanalysis was coupled to revisiting clinical phenotypes, models of inheritance and study approaches.

Results: Genetic diagnosis was reached in five families. Three families had novel mutations in known SCD genes. One family had novel mutation in a gene only recently identified to be associated with inherited neurological conditions. One family had a new gene not previously linked to monogenic diseases in humans. We were able to increase our overall success rate on WES analysis to 86% (12 out of 14 families).

Conclusion: Re-evaluation of genotypic and phenotypic data on undiagnosed individuals coupled to adoption of new analysis approaches and utilization of new technical advances can maximize the yield of WES analysis.   

 

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MOLECULAR BASIS OF HEREDITARY SPINOCEREBELLAR DEGENERATION

EXPLORING THE MOLECULAR BASIS OF HEREDITARY SPINOCEREBELLAR DEGENERATION IN A LARGE SUDANESE FAMILY

Arwa Babai1, Liena Elsayed2, Inaam Mohammed 3 , Ahlam Hamed3, Maha Elseed3, Elhami Alnaeem1,  Isra Eltazi1, Mohammad Mubarak2, Esra Emad2, Ashraf Mohammed2,4,5 , Shaimaa Omer M.A. Taha6

 

1Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.

2Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan.

3 Faculty of Medicine, University of Khartoum, Sudan.

4Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne  Universités, UPMC Universités Paris VI UMR_S1127, 75013 Paris, France.

5Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, 75013 Paris, France.
6Department of Radiology, Dar Al Elaj specialized hospital, Khartoum, Sudan.

 

ABSTRACT

Background: Spinocerebellar neurodegenerative disorders (SCD) are known for their complex phenotypic and genetic heterogeneity forming a heterogeneous spectrum of disorders with hereditary spastic paraplegias (HSP) on one end and hereditary ataxias (HA) on the other. In clinical practice, limb spastic weakness and cerebellar ataxia are frequently found together and present the hallmark of SCD. The genetics of SCD has been a target for extensive researches in many parts of the world, yet little is known about the genetics of SCD in Sub-Saharan African population.

Methods: In this study, we recruited a large consanguineous Sudanese family with five affected siblings. Genomic DNA was extracted and screened for genetic variations using whole exome sequencing (WES). Analysis was done to identify the culprit variations using bioinformatics tools and in-silico prediction of variants pathogenicity.

Results: Clinical results showed a complex phenotype of progressive spastic-ataxia complicated with deafness. Microcephaly was detected in the two eldest patients. Analysis of WES data and variant prioritization suggested two homozygous missense variants in two candidate genes (MYO15A and SEMA5D) that were not reported to be linked to similar disease before. The first variant in MYO15A gene (NM_016239.3: c.1634C>T) was reported to cause autosomal recessive hearing loss but was not reported to similar neurological disease. The second variant (NM_006378.3:c.1588G>A) was in SEMA4D gene which involved in brain development but not reported to be associated with inherited neurological conditions before. Both variants were extremely rare and highly conserved. They were predicted to be highly pathogenic using bioinformatics tools. 

Conclusion: The scarcity of genetic data in the highly consanguineous Sudanese population makes whole exome sequencing a powerful and cost effective strategy to identify both known and new pathogenic variations and genes. Sanger sequencing and further functional studies are recommended to prove the association of MYO15A gene and SEMA4D gene with the complex clinical phenotype of deafness, spasticity and ataxia.

Presenter: Dr. Arwa Babai          MBBS,  MSc

Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan

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Telomere length and Chronic stress

Telomere length and Chronic stress in internalizing mental disorders among HIV+ children and adolescents in Uganda

 

Introduction

Shorter telomere length has been associated with internalizing mental disorders (IMDs). However the nature of this association is yet to be elucidated.

 

Objective

We aimed at determining the longitudinal association between chronic stress and telomere length (TL) over a 12 months’ period.

 

Methods

In 368 children and adolescents with any IMDs and 368 age and sex matched controls, relative TL (RTL) was assessed. Hierarchical cluster analysis was used to generate the different chronic stress classes. Logistic regression analysis was used to model the association between chronic stress and RTL, controlling for age and sex.

 

Results

We observed a trend towards association between increased chronic stress and longer baseline RTL (p=0.067)

Analyzing both cases and controls, we observed a statistically significant difference between baseline and 12-month RTL (p<0.001). This difference remained significant when cases and controls were individually analyzed (p<0.001 respectively). We found no statistically significant association between chronic stress and the change in RTL after 12 months (p= 0.272).

 At baseline, cases were found to have significantly longer RTL compared to controls (p<0.001). Chronic stress had no mediating role in this association, since the p-value remained the same (p<0.001). Also, the observed difference in RTL between cases of IMDs and controls was not significant at the 12 month follow-up (p=0.117).  

Conclusion

Generally, there is a significant attrition in RTL over a 12 months’ period which is driven by IMDs. Baseline RTL are longer among cases of IMDs than controls. Longitudinal RTL is not associated with IMD.

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POLYMORPHISM  IN EXON 7 OF ENDOTHELIAL NITRIC OXIDE SYNTHASE

ASSOCIATION OF G894T POLYMORPHISM  IN EXON 7 OF ENDOTHELIAL NITRIC OXIDE SYNTHAESE  ( eNOS GENE ) WITH DIABETIC SEPTIC FOOT PREDISPOSITION IN SUDANESE

    Authors:

Shaza Esmat Omer Mohamed Ali ¹ , Mohamed Mahmoud Mohammed Ahmed ²,  and Manal Ahmed  M. A . Fadl³ .

¹ Department of Biotechnology ,Juba university .

 ² Fellowship  of Sudan Medical Specialization board

³Assistant professor of Molecular Biology –Alneelain  University

Diabetic septic foot is complication of diabetes and leads to amputation of extremities with high morbidity rate. In Sudan the prevalence of DSF is increasing and genetic role was evidenced .

The endothelial nitric oxide synthase (eNOS) encoded by the NOS3 gene is responsible for the synthesis of endothelium-derived nitric oxide (NO) with function include vasodilation  ,neurotransmitter, neuroprotective ,pain perception , and vasoprotective .The    polymorphism of G to T at nucleotide 894 in exon 7 of eNOS  gene  change    eNOS structural   and activity leading to   endothelial dysfunction and  then  impaired wound healing .

This  cross sectional study was carried out to examine the association of SNP (G894T) of  eNOS gene with Sudanese  DSF patients using blood sample from 53  diabetic patients as control and 62  DSF patients as cases  with clinical and demographic data   questionnaire without  restriction to age, gender, race or disease.

DNA from blood sample was extracted using guanidine chloride method and its   quality and quantity was  measured  using electrophoresis and nanaophoto-meter  respectively  and  then DNA was  amplified in PCR thermo cycler whereas genotyping and alleles percentages was detected using restriction fragment length polymorphism (RFLP) technique .

 Results showed no  association of G894T polymorphism of the (eNOS) gene with DSF  (P= 0.105)which may be explained by gene pools ,environmental factors and neuropathy  which detected in 68.8%of DSF increasing  the risk of DSF predisposition 3.7 folds   Moreover, the T mutant allele was frequent among both DSF(91.1%) and DM(81.1%)  patients .

Also high frequency of males among DSF(83.8%) with a significant gender difference between DSF and DM patients (P= 0.00)  may be attributed to smoking, sensitivity to insulin and negative  effect of androgens hormone on wound healing.

The low socioeconomic status among DSF (95.7%) was  significantly  difference   (P=0.00) which  may be regarding  to  lack of foot care and treatment  .

 

 

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Genetic epidemiology of rare autosomal recessive disorders and genome research 

Genetic epidemiology of rare autosomal recessive disorders and genome research 

 

Giovanni Romeo M.D.

European School of Genetic Medicine (www.eurogene.org)

 

Understanding the medical genetics needs of any inbred community requires the knowledge of a few basic concepts of genetic epidemiology. I will start from the theoretical foundations which predict the frequency of alleles associated with rare autosomal recessive (RAR) disorders and are based on the study of children of consanguineous marriages, as established in the pre-molecular era by the Swedish geneticst Dahlberg. He first noticed in 1943 that the proportion of consanguineous parents of children affected with any RAR disorder is inversely proportional to the frequency of the mutated gene in the general population (q). In Italy it was possible to calculate q for PKU, Friedreich ataxia and CF even before the cloning of the respective genes using the “Vatican Archive” of consanguineous marriages, created 50 years ago by Cavalli-Sforza and coworkers, which documents the variations in time and space of consanguineous marriages in the general population broken down for the different Italian regions and provinces for five years periods during almost 400 years (1600–1964).

The probability that a child of consanguineous parents carries two copies of the same allele identical by descent (IBD) is called autozygosity (=homozygosity by IBD). Then if one knows precisely the frequency of consanguineous marriages in the general population (C) for any given time period and population subgroup (e.g. from the Vatican Archive) and the proportion of consanguineous parents of children affected with a given RAR disorder (C’) in the same population, q can be accurately calculated following Dahlberg’s approach.

Today a more efficient epidemiological approach based no longer on demographic data but on molecular data (defined Homozygosity Index: HI) makes it possible to estimate q for a RAR disorder if one knows the mutational spectrum, the proportion of truly homozygous patients determined by mutation analysis and the inbreeding coefficient estimate (F) in a small sample of affected individuals. This result was achieved for PKU and Mediterranean Fever in Lebanon and Turkey, for  Wilson disease in Sardinia and more recently for Congenital Adrenal Hyperplasia ( CAH) in mainland Italy and Sardinia (Gialluisi et al. Clin. Genetics, 93, 223-227, 2018).

In conclusion these epidemiological studies based on consanguinity have originated an interesting strategy useful for planning public health policies regarding the prevention of RAR disorders in the genomic era. First of all, the inbreeding coefficient (F) can be calculated using genomic data (like SNP data) which make the HI approach easier and more precise. Moreover causative mutations associated with RAR disorders lie in Regions of Homozygosity (ROH) and can be identified more easily in consanguineous families, as done for example by Whole Exome Analysis in the case of the MYO15A frameshift duplication which represents the  major cause of Genetic Hearing Loss (GHL) in Oman (Pippucci et al. J. Human Genetics, 62: 259–264 (2017) doi:10.1038/jhg.2016.120).

 

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