World Kidney Forum

Consanguinity in Saudi Arabia: A Unique Opportunityfor Pediatric Kidney Research

Jameela A. Kari, MD, FRCP,1 Detlef Bockenhauer, MD, PhD,2 Horia Stanescu, MD, PhD,2

Mamdooh Gari, PhD,3 Robert Kleta, MD, PhD,2 and Ajay K. Singh, MBBS4

Identification of disease-related genes is a critical step in understanding the molecular

basisofdiseaseanddeveloping targeted therapies.Thegenetic studyofdiseasesoccurring

in the offspring of consanguineousunions is a powerful way to discover newdisease genes.

Pediatric nephrology provides an excellent example because w70% of cases of kidney

disease in childhood are congenital with a likely genetic basis. This percentage is likely to be

even higher in countries with a high consanguinity rate, such as the Kingdom of Saudi

Arabia. However, there are a number of challenges, such as cultural, legal, and religious

restrictions, that should be appreciated before carrying out genetic research in a tradition-

bound country. In this article, we discuss the background, opportunities, and challenges

involved with this unique opportunity to conduct studies of such genetic disorders. Keys to

success include collaboration and an understanding of local traditions and laws.

Am J Kidney Dis. -(-):---. ª 2013 by the National Kidney Foundation, Inc. Published

by Elsevier Inc. All rights reserved.

INDEX WORDS: Consanguinity; genetic disease; linkage analysis; gene discovery;

identical by descent (IBD); homozygosity mapping; kidney research; pediatrics;

population differences; Saudi Arabia.

WKF Advisory Board

John T. Harrington, MDBoston, Massachusetts

Rashad S. Barsoum, MDCairo, Egypt

Christopher R. Blagg, MDMercer Island, Washington

John Boletis, MDAthens, Greece

Garabed Eknoyan, MDHouston, Texas

Tazeen H. Jafar, MD, MPHSingapore

Nestor Schor, MD, PhDSao Paulo, Brazil

The past decade has seen an ex-plosion in the elucidation of

Mendelian disorders. This has beenmade possible by the deciphering ofthe human genome and the develop-ment of new next-generation

From the 1Department of Pediatrics,Faculty of Medicine, King AbdulazizUniversity, Jeddah, Kingdom of SaudiArabia; 2Institute of Child Health, Uni-versity College London, London, UnitedKingdom; 3Center of Excellence inGenomic Medicine Research, King Abdu-laziz University, Jeddah, Kingdom ofSaudi Arabia; and 4Renal Division, Brig-ham and Women’s Hospital, HarvardMedical School, Boston, MA.Received April 16, 2013. Accepted in

revised form August 2, 2013.Address correspondence to Jameela A.

Kari, MD, FRCP, King Abdulaziz Uni-versity, PO Box 80215, Jeddah 21589,Kingdom of Saudi Arabia. E-mail: jkari@doctors.org.uk� 2013 by the National Kidney Foun-

dation, Inc. Published by Elsevier Inc. Allrights reserved.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2013.08.033

Am J Kidney Dis. 2013;-(-):---

sequencing technologies.1 Never-theless, to date, only about 2,000-3,000 of the estimated 25,000protein-coding genes have beenlinked to disease, with several thou-sands more expected to be diseaserelated.2 Identification of these genesis hampered because many of thesedisorders are very rare and casestherefore appear to be sporadic andthusmaynotbe recognizedashavinga genetic cause. Even when the dis-order is believed to be genetic, iden-tificationof theunderlyingmutationsis difficult becausewe all carrymanythousands of such variants in ourgenome and, in most cases, sortingthe causative ones from all the othervariants is extremely difficult, if notimpossible. This is where geneticstudies of consanguineous pop-ulationspresent auniqueopportunityfor disease gene discovery.

CONSANGUINITY, LINKAGEANALYSIS, AND GENE

DISCOVERY

For many of the disease genesthat have been identified to date,the studies have been performed

in families from geographicallyor culturally isolated popula-tions. The success of mappingdisease-causing genes in isolatedpopulations is related mainlyto chromosomal stretches beinginherited identical by descent(IBD), that is, when a part of thechromosome inherited from thefather has the same sequence asthe corresponding part of thehomologous chromosome inheri-ted from the mother.3 When par-ents are related, there is a greaterlikelihood of the offspring inher-iting autosomal recessive condi-tions, but this relatedness alsomakes it more probable thatdisease-causing mutations occurin blocks of homozygosity. Thus,looking at blocks of homozy-gosity in such populations canhelp researchers hone in on theregion of the causative mutation.

An example is given in Fig 1,which shows a pedigree of arare autosomal recessive disease(Fig 1A) and a schematic ofthe mutation-mapping process(Fig 1B). For a simple Mendelian

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Figure 1. Genetic mapping in aconsanguineous pedigree. (A) Pedi-gree of a family affected with EAST(the presence of epilepsy, ataxia,sensorineural deafness, and tubulop-athy) syndrome. The disease allelewas present in one of the ancestorsin the first generation of the familyand transmitted through the genera-tions. The affected children in theyoungest generation then inheritedthe disease allele from both parents,resulting in homozygosity for theallele. While the statistical risk foreach child to inherit the disease allelefrom both unaffected parents is 25%(1 in 4), in one branch of this family,all 3 children happened to beaffected. (B) Identity by descent isdemonstrated by haplotype analysis.In this case, chromosomes weremapped by determining single-nucleotide polymorphisms (SNP)along the chromosomes. Individualscan be either type 1 or type 2 for theindividual SNP. All affected membersare homozygous for the disease allele(boxed region). The region in whichthe disease allele must occur hasbeen limited by recombination eventsin EAST 1-1 and EAST 1-2. Adaptedfrom Bockenhauer et al4 with permis-sion of the Massachusetts MedicalSociety.

Kari et al

disease transmitted in an autosomalrecessive manner, the affectedpatient inherits the causative IBDallele from both parents. It originatesin a common ancestor and is trans-mitted through different branches ofthe pedigree and united through theconsanguineous bond (indicated bydouble lines in the pedigree). In anychild born from such a consanguin-eous union, there will be severalhomozygous chromosomal regionsof IBD, but one region (thatharboring the variant that is causalfor the trait) will be shared betweenindividuals expressing the trait,while not being homozygous in in-dividuals who do not express thetrait.With each recombination of thechromosomes during meiosis, theborders limiting the IBD alleles maybe narrowed, leading to a situation asshown in Fig 1B, in which therecombination events have limitedthe stretch of IBD to a very shortregion.

2

The possibility of detectingstretches of homozygosity byassessing genetic markers on theDNA of individuals in inbred/consanguineous pedigrees estab-lished the practical foundationsof the homozygosity mappingapproach to positional cloning.5

Although the probable cause of arare autosomal recessive trait in aconsanguineous family is IBDhomozygosity, there also is thesame risk as in the offspring ofnonconsanguineous unions ofcompoundheterozygotemutations,which will be missed by strict ho-mozygosity mapping.6 Therefore,the analysis is better performed insuch a way as to also identifylinkage in regions of compoundheterozygosity.7 New sequencingtechnologies, such as wholeexome or genome sequencing, aredramatically speeding up the paceof gene discovery.1 However, themore DNA being sequenced, the

more variants identified, and thechallenge remains to identify thedisease-causing mutation amidthe noise of the many otherchanges. For this reason, it remainsimportant to combine these newtechnologies with mapping strate-gies, such as linkage analysis, tonarrow the focus in the searchfor the disease allele.

GENETIC CONSEQUENCES OFCONSANGUINITY

The exact risk of consanguin-eous unions to the health of theprogeny is difficult to determinebecause of confounding factors,such as living standards andavailable levels of health care. Onelarge study reported an excessrisk of 4.4% of prereproductivedeath in offspring of first-cousinmarriages.8 Other studies havereported an excess risk of birthdefects of 0.7%-3.8%.9 How-ever, these numbers have to be

Am J Kidney Dis. 2013;-(-):---

Table 1. Summary of Published Descriptive Studies From Saudi Arabia

Type of Kidney Disease Main Findings Study

Polycystic kidney disease 15 children, diagnosed at a median age of 10 mo,

with a better prognosis for those diagnosed after

6 mo of age

Matto et al16 (1994)

Primary hyperoxaluria type 1 (PH1) 16 children presented with nephrocalcinosis and chronic

kidney failure

Snajad et al17 (1999)

Distal renal tubular acidosis (dRTA) 7 patients with the autosomal recessive inherited syndrome

of dRTA and sensorineural hearing loss

Zakzouk et al18 (1995)

Familial hypomagnesemia with

hypercalciuria and

nephrocalcinosis (FHHNC)

7 children with similar clinical and biochemical data to

previous reports; however, they tend to show a slower

rate of progression to end-stage renal disease

Kari et al19 (2003)

Fanconi-Bickel syndrome 10 patients with impaired glucose tolerance/diabetes range

hyperglycemia after oral glucose tolerance test

Taha et al20 (2008)

Consanguinity and Pediatric Kidney Research

interpreted with caution becausethey may be influenced by social,economic, or demographic factors;differences in reproductive be-havior; and early- and late-onsetmorbidity and mortality.8-10

PATTERNS OF CONSANGUINITY

Consanguinity is present inw10% of the global population.11

Although consanguinity now tendsto be frowned upon in theWest, thishas not always been the case. Inboth Europe and the United States,marriages among first cousins werecommon and widely encouragedthrough the mid-19th century. Afamous example is that of CharlesDarwin, who married his firstcousin Emma Wedgwood andremarked: “the widely differenthabits of life of men and women incivilized nations, especially amongthe upper classes, would tend tocounterbalance any evil from mar-riages between healthy and some-what closely related persons.”12

Consanguinity in Western coun-tries now is limited mostly to immi-grant communities. For example,55% of marriages between Mirpuri(Kashmiri) Pakistani Muslim im-migrants in theUnitedKingdom arebetween first cousins.11,13,14

Although consanguineous unionsof first cousins are permissiblein most religions (some, eg, theRoman Catholic and EasternOrthodox Churches, require special

Am J Kidney Dis. 2013;-(-):---

dispensation), nowadays consan-guinity is most common inMuslim-majority countries. TheKoran does not contain any spe-cific encouragement of the prac-tice,9 and one of the hadith(recorded instructions from theProphet Mohammed) actually dis-courages marriage within thefamily. Yet the Prophet Moham-med married his daughter Fatimahto his cousin Ali, so consanguin-eousmarriage can be interpreted asfollowing the example of theProphet. The origins of consan-guineous marriage in the Arabworld date back to pre-IslamicArab traditions in which first-cousin marriages of the paternalsubtype (parallel cousin marriagesbetween a man and his father’sbrother’s daughter) were encour-aged. The origins of this traditionlikely are social and economic: incommunities in which the womanis married off to the husband’sfamily, treatment of the woman isexpected to be more congenial ifshe already is part of the family.And in communities in whichdowry payments are custom,intrafamilial marriages minimizethese costs or at least keep themwithin the family.

In present-day Saudi Arabia,.50% of all marriages are con-sanguineous (marriages betweencousins).15 The actual degree ofinbreeding is compounded further

by the high frequency of mar-riages occurring within a clan,tribe, or caste.

CONSANGUINITY AND THESTUDY OF GENETIC DISEASES

OF THE KIDNEY IN THEKINGDOM OF SAUDI ARABIA

Overview

More than 70% of kidney dis-eases in children have a geneticcause.1 In the Kingdom of SaudiArabia, although very limitedepidemiologic data exist, it islikely that because of consan-guinity, genetic causes accountfor the vast majority of kidney dis-orders (Table 1).16-20 Consanguin-ity is the most obvious explanationfor the high rate of autosomalrecessive diseases observed inSaudi Arabia.21 Preliminary obser-vations indicate that childrenin Saudi Arabia, compared withchildren in other parts of theworld, appear to have a higherincidence of familial juvenilenephronophthisis; polycystic kid-ney disease; tubular diseasessuch as familial hypomagnese-mia, hypercalciuria, nephrocalci-nosis syndrome, and renal tubularacidosis; congenital urologicanomalies; and familial nephroticsyndrome.21 This pattern is similarto that observed in Lebanon,22

Turkey,23 and Kuwait,24 whereconsanguinity also is common.

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Box 1. Centers for Genetics in Saudi Arabia and Representative Publications

� King Faisal Specialist Hospital and Research Centre (Riyadh)

> Department of Genetics, Research Centre: A molecular genetic analysis of

childhood nephrotic syndrome in a cohort of Saudi Arabian families32

> Stem Cell Therapy and Tissue ReEngineering Program: Genetic diagnosis in

consanguineous families with kidney disease by homozygosity mapping

coupled with whole-exome sequencing31

� Saudi Diagnostic Laboratory (Riyadh)

� King Abdulaziz University (Jeddah)

> Center of Excellence in Genomic Medicine Research: Mutational screening of

RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid

carcinoma33

> Princess Al-Jawhara Center of Excellence in Research of Hereditary Disor-

ders: Knowledge regarding the national premarital screening program among

university students in western Saudi Arabia34

� King Abdulaziz Medical City at National Guard Hospital (Riyadh)

Kari et al

The rate of consanguinitymeans that some genetic kidneydiseases have been detected forthe first time in Saudi Arabia. Forexample, Ohlsson et al25 pub-lished the first report of a syn-drome of “marble brain disease”comprising osteopetrosis, renaltubular acidosis, and cerebralcalcification. Marble bone diseaseis associated with intellectualdisability and stunted growth andhas been linked to carbonicanhydrase II enzyme deficiency.26

Long-term follow-up of childrenwith this disease also has beenreported from Saudi Arabia.27

Other new associations also havebeen discovered in Saudi Arabiaand reported as a basis for newsyndromes.28-30 In recent years,new high-throughput genotypingand sequencing technologies havebecome available, which assist inmutation detection in known dis-ease genes in individuals withinherited kidney disease.31 In thisworkflow, whole-genome single-nucleotide polymorphism analysiscoupled with exome sequencing ongenomic DNA samples fromaffected members of families withinherited kidney disease facilitatesthe detection of culprit genes inkidney diseases with overlappinghistopathologic features.

Resources

There is substantial opportu-nity for research in genetically

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transmitted diseases in SaudiArabia, with increasing recognitionof the need for multiple geneticcenters. A number of geneticresearch centers have been estab-lished (Box 1) in 2 larger cities(Riyadh and Jeddah). Althoughother cities inSaudiArabia lack suchcenters, developing experience inresearching genetic diseases hasbeen strongly supported by thegovernment of Saudi Arabia.

King Abdulaziz University’sCenter of Excellence in GenomicMedicine Research and the divi-sion of Pediatric Nephrologyrecently established a formalcollaboration with UniversityCollege London in the UnitedKingdom. In addition, there isongoing collaboration with theUniversity of Michigan andHarvard Medical School in theUnited States. Through these col-laborations, all children withcongenital nephrotic syndromeand steroid-resistant nephroticsyndrome are screened for muta-tions in NPHS1 (nephrin), NPHS2(podocin), andWT1 (Wilms tumorprotein).35 Patients for whommutations in known disease genesare not detected then will beincluded in projects for the iden-tification of new disease genes.The collaborations aim to transferknowledge between the centers toimprove understanding of genetickidney disease in general and inSaudi Arabia specifically.

The Importance of UnderstandingTradition

Pursuing studies in consan-guineous populations in SaudiArabia or elsewhere in the worldrequires an appreciation of thechallenges that tradition and cus-toms pose for screening andtreating genetic disease. Althoughthe opportunities for investigatingthe genetics of kidney disease inconsanguineous populations areexceptional, there are a number ofchallenges. Chief among these arethe cultural, legal, and religiouslimitations posed by a tradition-bound country. Screening for ge-netic diseases is very importantfor clinical care, as well as thestarting point to the genetic dis-covery process, but families mayfear being stigmatized by theircommunity. Although there is noexplicit religious restriction re-garding genetic research, thediagnosis of a genetic disease canresult in feelings of inferiority andshame and in reduced chance ofmarriage for other members of thefamily, in a culture in which mostmarriages are arranged. In addi-tion, there are legal issues aroundinternational genetic studiesbecause the movement of DNAmaterial outside Saudi Arabia isrestricted.36

Screening for Genetic Disease

In Saudi Arabia, screening forgenetic disease is endorsed by thegovernment through royal decreesand fatwas; however, the practiceand enforcement of these rulingscan be variable. Some of the rulesalso are conflicting, adding con-fusion to the situation. In addition,genetic screening is not offered forall genetic diseases. For example,a royal decree passed in 2003mandates a premarital screeningtest followed by nondirective ge-netic counseling for hemoglobin-opathies, but not for any of thegenetically transmitted kidneydiseases. Termination of preg-nancy in the first 120 days after

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Consanguinity and Pediatric Kidney Research

conception is permitted though a1990 ruling (Fatwa) if there is asevere untreatable malformationin the fetus,37 but prenatal diag-nosis and termination of preg-nancy are not offered to carriercouples. In Saudi Arabia, pregnantwoman receive routine ultrasoundscanning during their first ante-natal visit. Pretest information isusually provided to the coupleregarding possible abnormalitiesthat could be found and anexplanation of possible conse-quences.38 If the results indicatean abnormality, the woman will bereferred for a detailed anomalyscan, and further invasive tech-niques, such as amniocentesis,might be offered.In routine prenatal ultrasound

screening in Saudi Arabia, renalanomalies are reported to bedetected in 0.7% of screenedfetuses, which is similar toother countries.38,39 However, theavailability and accuracy of ultra-sound screening often are limitedin rural areas and small cities. Inlarger cities, the situation is better,but still not always ideal. A studyfrom Riyadh found that the ante-natal detection rate of posteriorurethral valve was only 27%,which is substantially lower thanthe international rate of 70%.40 Ifa severe genetic or congenitaldisorder is detected, the couplehas to face the major decision ofwhether to terminate the preg-nancy. This is performed in a fewcenters, but often leads to ethicaldilemmas. However, social atti-tudes are changing and becomingmore accepting of termination ofpregnancy in some conditions.41

Biochemical neonatal screeningprograms for congenital hypothy-roidism were first begun in SaudiArabia in 1985,37 and by 1991,such screening was available at20 centers. In 2005, a nationalscreening program started, and by2008, it covered 400,000 new-borns overall. Electrospray tan-dem mass spectrometry was first

Am J Kidney Dis. 2013;-(-):---

used for neonatal screening of 16inherited metabolic diseases in1995 and in 2005 was establishedon a national scale, now reachingalmost 90% of all newborns inSaudi Arabia.41 However, thereare geographic limitations in theavailability of physicians whohave the specific expertise neededfor many of the rare conditions.Also, there is a large needfor additional training and educa-tion about the disorders that maybe detected through newbornscreening programs. Unfortu-nately, while many programsprovide for screening and diag-nosis, most have limited resourcesfor long-term management, in-cluding the provision of necessarytreatment and services, which maydefeat the purpose of these vitalscreening programs.42

Storage and Use of Samples

A national biobank has beenestablished only recently in theKingdom and to date, DNA,RNA, and plasma samples arestored mainly at local geneticcenters. Deposited material in-cludes tumor tissue, as well asselected DNA and RNA samples,which are not collected systemat-ically, but by interested clinicians,as well as by disease-specific in-vestigators. Consent for samplecollection is obtained through in-dividual research protocols.

A bylaw to the regulationsgoverning research ethics withrespect to living creatures wasproduced by the National Com-mittee for Bioethics in SaudiArabia, which regulates all mattersof scientific research, includingdealing with and researching ge-netics materials.36 It states thatgenetic research should be in linewith Islamic values, local culture,and environmental safety stan-dards. The bylaw further stipu-lates that the analysis should beperformed in accordance withthe practices of internationallyrecognized research on genetic

material. It regulates saving thegenetic data in the local geneticsbanks, which feed it to a centralrepository at King Abdullah Cityfor Science and Technology.

An important aspect of thebylaw is that genetic materialshould be analyzed within SaudiArabia if possible. However,such material can be sent acrossthe borders43 provided that anumber of conditions are met.First, the destination must be aknown research center with agood reputation; there shouldbe a signed contract to protectthe national rights (includinginvolvement in decisions andrecognition of all proceduresdone with samples, as well asrights in publications) and rightsof all parties. Second, the con-tract should be agreed to by thelocal administration (if it ispossible to do the same researchthrough national collaborations,this is preferred). Third, samplesshould be coded so that studiedindividuals will not be identifi-able. In addition, approval of alocal ethics committee can beoverridden by the national com-mittee, which retains the right(which should be made clear inthe contract) to stop the researchif they find that it is not usefulor is harmful to the Saudi soci-ety. It is permissible to sendsamples for diagnostics testsprovided that the tests are notavailable in Saudi Arabia.43

Genetic Counseling

Genetic counseling by a genet-icist or genetic counselor is avail-able only in select centers. Forgenetic kidney diseases, coun-seling usually is done by thenephrologist involved in request-ing the analysis.

SUMMARY

The next frontier in geneticdiscovery for kidney disease inchildren arguably lies in ex-ploring rare and complex genetic

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Kari et al

disorders. A highly consanguin-eous population such as in SaudiArabia presents a unique oppor-tunity to conduct such studies.Examples from other disciplines,such as genetic discovery inautism,44 provide a model for howthis can be done successfully.Keys to success include collabo-ration and an understanding oflocal traditions and laws.

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: The authors

declare that they have no relevant financialinterests.

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