Table 8 Evaluation of the identified variants for observation as Arab mutations in Arab studies.

rs137853054 (G_A)

PARK2

Parkinson disease, juvenile, type 2; (PMIM:600116). GARD lists this as rare disorder. OMIM lists single gene⁹²;

Pathogenic and rare disorder

AR

0/2/288

0.0034/0.0002/0.0025

17/1.3503

rs61754375

(G_A)

TYR

Tyrosinase-negative oculocutaneous albinism, Type IA; (PMIM:203100) – OMIM lists single gene¹⁰⁸;

Pathogenic and rare disorder

AR

0/1/286

0.0017/0.0002/.

8.5/.

rs121964924 (A_G)

DPYS

Dihydropyrimidinase deficiency; (PMIM:222748) – OMIM lists single gene¹⁰⁹;

Pathogenic and rare disorder

AR

0/1/289

0.0017/0.0002/0.0020

8.5/0.8424

rs58331765 (C_T)

ABCA4

Stargardt disease 1; (PMIM:248200) – OMIM lists two genes⁹³;

Pathogenic and rare disorder

AR

0/2/288

0.0034/0.0028/0.0005

1.2143/6.7460

rs61757294 (A_G)

CYP11B2

Corticosterone methyloxidase type 2 deficiency. (PMIM: 610600)¹¹⁰. this cited study is on Iranian-Jewish origin patients.

Pathogenic and rare disorder

DR; this and rs28931609 to be homozygous.

??

0.1519/0.0531/?

For variants of DR mode of inheritance higher MAF is alright though it is a pathogenic variant.

2.8606/?

rs1801280 (T_C) NAT2

Slow acetylator due to N-acetyltransferase enzyme variant; (PMIM:243400) – OMIM lists single gene¹¹¹;

Drug Response

AR

41/134/100

0.3927/0.2927/0.4340

1.3416/0.9047

rs79204362 (C_T)

CYP1B1

Early onset of Glaucoma, digenic; (PMIM: 231300) – OMIM lists single gene¹¹²; This is a rare disorder but reaches high prevalence in Saudi Arabian populations.

Pathogenic and rare disorder; 11–50

AR

0/6/284

0.010/0.004/0.013

CTGA reports 1 in 2,500 among Saudi Arabians. MAF is only marginally higher at 1.03%.

2.4587/0.7553

rs61732874 (C_A)

MEFV

Familial Mediterranean Fever (FMF) Recessive; (PMIM: 249100) – OMIM lists single gene¹¹³;

Pathogenic; rare disorder 51–100

AR

0/9/278

0.015/0.001/0.012

FMF is a rare disorder in Europe; it is no longer rare in certain populations¹⁰⁵. CAGS’ incidence is 51–100; varies 1/2000 to 1/100 in eastern Mediterranean populations. Thus, MAF of 1.55% is acceptable for pathogenic variant.

8.6026/1.2281

rs121908530 (G_A)

AGXT

Type 1 primary Hyperoxaluria (PMIM: 259900) – OMIM lists single gene¹¹⁴;

Pathogenic; rare disorder

?

0/1/290

0.001718/./.

./.

rs587776954 (A_G)

C12orf57

Temtamy syndrome (PMIM:218340) – OMIM lists single gene¹¹⁵;

Pathogenic; rare disorder

AR

0/2/288

0.003436/./0.003021

./1.1374

rs61747728 (C_T)

NPHS2

Susceptibility to Nephrotic syndrome, type 2 (PMIM: 600995) – OMIM lists single gene¹¹⁶;

Risk factor for rare disorder. 11–50

AR

0/8/281

0.01375/0.0145767/0.012085

0.9433/1.1377

rs1799945 (C_G)

HFE

Type 1 Hemochromatosis - microvascular complications of diabetes, susceptibility to, 7, included (PMIM:235200). OMIM lists two genes^117,118,119;

Risk factor for common disorder; >100

AR

4/63/224

0.122/0.073/0.119

1.6693/1.0180

rs1801131 (T_G)

MTHFR

Schizophrenia; sczd (PMIM:181500) – OMIM lists several genes¹²⁰;

Risk Factor; complex disorder; >100

AD

31/128/132

0.3265/0.3264/0.3353

1.0001/0.9736

rs77775126 (C_T)

RP1

Retinitis pigmentosa 1 (PMIM: 180100) – OMIM lists single gene^121,122.

Risk factor by inference for common disorder; 11–50

AR

0/11/280

0.0189/0.0189/0.0181

0.9999/1.0426

rs1801133 (G_A)

MTHFR

Susceptibility to T2DM in Lebanese^123,124.

Risk Factor; complex disorder

AR

12/81/197

0.1810/0.2454/0.2557

0.7376/0.7077

rs1801131 (T_G)

MTHFR

Protective effect: T2DM in Israel Jews and South Indians^123,125.

Risk Factor; complex disorder

AD

31/128/132

0.3265/0.2494/0.3353

1.3091/0.9737

rs1042713 (A_G)

ADRB2

PharmGKB: drug response to asthma. OMIM: susceptibility to asthma, nocturnal PMIM:600807). Arab study: susceptibility to early onset obesity and insulin resistance^96,102.

Drug response; complex disorder

AD

82/126/55

0.5513/0.5244/0.5645 A->G (Arg16Gly) is causative; hence the frequencies of the risk allele G rather than the minor allele are listed.

1.0513/0.98

rs1042714

ADRB2

PharmGKB: drug response to asthma. OMIM: susceptibility to obesity and to childhood asthma. PMIM: 601665. Arab study: for Coronary artery disease/myocardial infarction^103,104.

Drug response; complex disorder

AR

19/90/176

0.2246/0.2053/0.2412

1.094/0.9312

rs1805087 (A_G)

MTR

PharmGKB: drug response to Rheumatoid arthritis. OMIM: does not list. Arab study: for Autism – North Iran⁹⁷.

Drug response; complex disorder

GG is the risk factor.

23/105/162

0.2603/0.2183/0.2021

0.2603/0.2021

rs1042522 (G_C)

TP53

PharmGKB: drug response to stomach neoplasm. OMIM: smoking related accelerated decline in lung function PMIM:608852; Arab study: in susceptibility to Breast Cancer in Tunisia⁹⁸.

Drug response; complex disorder

??

57/140/90

0.4425/0.5429/.

0.815/.

rs1800497 (G_A)

ANKK1

PharmGKB: drug response to Schizophrenia. OMIM: Taq1A polymorphism associated with neuropsychiatric disorders. Arab study: risk factor for Schizophrenia (PMIM:181500) in Egyptians⁹⁹.

Drug response; complex disorder

AD?

7/85/197

0.1713/0.3257/0.1908

0.5259/0.8975

rs1801058 (T_C)

GRK4

PharmGKB: drug response to Hypertension. OMIM: does not list. Arab study: risk factor for myocardial infarction among hypertensive subjects in Jordan¹⁰⁰.

Drug response; complex disorder

AD?

16/101/173

0.2293/0.3067/0.292

0.7476/0.7079

rs699 (A_G)

AGT

PharmGKB: drug response to Hypertension. OMIM: susceptibility to Essential hypertension (PMIM:145500). Arab study: Reduced life-span through genetic susceptibilities to Hypertension and Myocardial Infarction in UAE¹⁰¹.

Drug response; complex disorder

Mu?

91/127/47

0.583/0.7051/0.5534

0.8268/1.0535

rs28940872 (C_T)

ACADS

Scad deficiency (PMIM:606885). Single gene listed in OMIM.

Pathogenic; rare disorder;

AR

0/1/289

0.0017/0.0002/0.0015

8.5/1.1251

rs28941785 (C_T)

CTH

Cystathioninuria (PMIM:219500). Single gene listed in OMIM.

Pathogenic; rare disorder;

AR.

0/2/281

0.0035/0.0026/0.0065

1.3461/0.5347

rs28940885 (C_T)

GALE

Galactose Epimerase Deficiency (PMIM:230350). Single gene listed in OMIM.

Pathogenic; rare disorder;

AR

0/1/290

0.0017/0.002/0.0025

0.85/0.6751

rs114817817 (C_T)

SRGAP1

Susceptibility to Thyroid cancer, nonmedullary 2, (PMIM:188470). OMIM lists three genes for this disorder.

Risk Factor; common disorder

AD; (AR,AD,MF)

0/1/285

0.0017/0.0006/0.0070

2.8333/0.2415

rs6504649 (C_G)

THR801ARG

XYLT2

Pseudoxanthoma elasticum, modifier of severity. (PMIM:264800). OMIM lists three genes.

Risk Factor; common disorder

AR

60/136/94

0.4414/0.251/0.3962

1.7586/1.1139

rs118204113 (G_A)

HMBS

Acute intermittent porphyria (PMIM:176000). Single gene listed in OMIM.

Pathogenic; rare disorder

AD

0/1/289

0.001718/./0.000504

./3.4087

rs4149584 (C_T)

TNFRSF1A

Familial periodic fever, autosomal dominant. (PMIM:142680). Single gene listed in OMIM.

Pathogenic; rare disorder; 51–100

AR

0/4/287

0.0069/0.0069/0.0121

1.0000/0.5687

rs56208331 (G_A)

GATA4

Tetralogy of fallot (PMIM:187500). Single gene listed in OMIM.

Pathogenic; rare disorder; 51–100

AD

0/2/289

0.0034/0.0034/0.0025

0.9998/1.3645

rs104893836

(T_C)

GNRHR

Hypogonadotropic hypogonadism 7 without anosmia. (PMIM:146110). Single gene listed in OMIM.

Pathogenic; rare disorder

AR

0/1/290

0.0017/0.0012/0.0055

1.4167/0.3069

rs2476601 (A_G)

PTPN22

Susceptibility to T1DM (PMIM:222100). Also associated with susceptibility to Systemic lupus erythematosus (PMIM:152700). OMIM lists multiple genes.

Risk Factor; common disorder

AR

0/5/280

0.0292/ 0.0274/0.0131

1.00/0.98

rs17158558 (C_T)

RET

Susceptibility to hirschsprung disease 1 (PMIM 142623). Single gene listed in OMIM.

Risk Factor; common disorder

AD

0/15/273

0.02577/0.0219649/0.045867

1.1732/0.5618

rs121918219

(G_A)

VANGL1

Susceptibility to neural tube defects. (PMIM: 182940); OMIM lists 5 genes.

Risk Factor; common disorder; >100

AD

0/1/289

0.001718/./0.001007

./1.7060

rs121908736 (G_A) ADA

Partial adenosine deaminase deficiency (PMIM:102700).

Arab studies: CAGS reports another mutation from the same gene p.Arg282 > Gln¹²⁶.

Pathogenic; rare disorder

AR, SM. Compound heterozygosity

0/2/285

0.0035/0.0018/0.0005

1.9444/6.9444

rs61757582 (G_A)

DHCR7

Smith-Lemli-Opitz syndrome (PMIM:270400).

Arab studies: N287K (861 C > A); R352Q (1055 G > A) (rs121909768; seen in OMIM); and R352L (1055 G > T)¹²⁷.

Pathogenic; rare disorder

AR

0/1/284

0.0018/0.0002/.

9/.

rs61753185^$ (G_A)

TYR

Tyrosinase-negative oculocutaneous albinism, Type IA (PMIM:203100). Arab studies: c.817 G > C/p.W272C (rs62645902; not seen in OMIM)^108,128.

Pathogenic; rare disorder

AR

0/1/290

0.0017/0.0004/0.0005

4.25/3.3730

rs116100695 (G_A)

PKLR

Pyruvate kinase deficiency of red cells (PMIM:266200). Arab studies: 1058 C > T; Thr353Met (rs74315362 seen in OMIM)¹²⁹.

Pathogenic; rare disorder

AR

0/2/289

0.0034/0.0016/0.0096

2.125/0.3547

rs41295338 (G_T)

TGM1

AR congenital ichthyosis 1 (PMIM:242300). Arab studies: Compound heterozygosity for missense mutations (R141H- rs121918718, R142H-rs121918719), (p.Tyr136Ter-rs1057517836), (p.Ser326Cysfs*8), and Leu362Arg^130,131

Pathogenic; rare disorder

AR

0/2/288

0.0034/0.0022/0.0060

1.5454/0.5627

rs121434513 (G_C)

PNKD alias MR1

Paroxysmal Nonkinesigenic Dyskinesia 1 (PMIM: 118800). Arab studies: c.20 C > T; A7V rs121434512 – seen in OMIM¹³².

Pathogenic; rare disorder

AD

0/1/289

0.0017/0.0002/0.0005

8.5/3.3530

rs34424986 (G_A)

PARK2

Parkinson disease, juvenile, type 2. (PMIM:600116). Arab studies: exon 4 deletion and a 2-base AG deletion in exon 2 (101–102) from the same gene associated with the disorder¹³³. Not seen in OMIM. This table reports another variant rs137853054 seen in Arab study and in Kuwaiti exomes^133,134,135.

Pathogenic; rare disorder 11–50

AR

0/2/289

0.0034/0.0004/.

8.5/.

rs12021720 (T_C)

DBT

Maple syrup urine disease, intermediate, type II (PMIM:248600). Arab studies: c.1281 + 1 G > T in one patient from UAE. Not seen in OMIM¹³⁶.

Pathogenic; rare disorder

AR

5/67/218

0.1347/0.1082/0.12

The variant is in compound heterozygosity with [rs121965001]⁴⁶. Hence high MAF is acceptable.

0.97/0.98

rs1800858 (G_A)

RET

Susceptibility to Hirschsprung disease 1; HSCR1 (PMIM: 142623). Arab studies: c.1852T > C Cys618Arg mutation rs76262710. Seen in OMIM (for neoplasia)^137,138.

Risk Factor; common disorder; 11–50

AD

25/128/138

0.3058/0.2464/0.2593

1.24/1.1793

rs121918530 (A_G)

MEF2A

Coronary artery disease/myocardial infarction (PMIM:600660). Arab studies: (rs1059759 G > C) in Saudi Arabian patients¹³⁹.

Risk factor by inference for complex disorder.

AD

0/6/284

0.01031/0.000399361/0.002014

25.8162/5.119

rs11909217 (C_T)

LIPI

RARE & DELETERIOUS

Susceptibility to Hypertriglyceridemia, Familial (PMIM: 145750). OMIM lists LIPI and APOA5 for the disorder. Arab study: 3′ UTR C > G variant from APOC3 (not seen in OMIM or our exomes)⁹⁵. This is an inherited common disorder.

Risk factor by inference; common disorder.

AD

0/10/280

0.0172/0.006/0.01309

2.8667/1.3138

rs3135506 (G_C)

APOA5

CAGS VARIANT

Risk factor; Common disorder

AD

1/22/267

0.04124/0.0557109/0.070565

0.7402/0.5844

rs28932472 (G_C)

POMC

RARE & DELETERIOUS

Obesity, early-onset, susceptibility to (PMIM: 601665). OMIM lists several genes. Arab study: rs1042713: Arginine 16 Glycine (Arg16Gly) polymorphism in ADRB2 gene; which is associated with susceptibility to nocturnal asthma in OMIM and our study. rs1042713 A_G: (AA:55, AG:126, GG:82) & (MAF_KWT, 1KGP, GME: 0.5513/0.5244/0.5645)¹⁰².

Risk Factor;

common disorder

AR,AD,MF

0/1/287

0.0017/0.0024/0.0005

0.7083/3.3730

rs34911341 (C_T)

GHRL

RARE & DELETERIOUS

Risk Factor; common disorder

AR,AD,MF

0/1/290

0.0017/0.0026/0.0035

0.6538/0.4823

rs2282440 (G_A)

SDC3

CAGS variant

Association variant; common disorder; >100

AD

0/11/280

0.0189/0.0189/0.0282

0.9999/0.6703

rs11558538 (C_T)

HNMT

SAFD variant

Susceptibility to Asthma (PMIM: 600807). OMIM lists several genes.

Arab studies: 786 T > C [rs2070744] from the 5’ flanking region of NOS3 (OMIM lists this variant but the variant is not seen in Kuwaiti exomes)¹⁴⁰.

Risk Factor for common disorder

AD

7/55/212

0.1259/0.0595/0.0968

2.1159/1.3009

rs1801483 (G_A)

GCGR

SAFD Variant

T2DM (PMIM: 125853).

Arab studies: Ala222Val (rs1801133 C > T AR/AD) mutation from MTHFR gene in Lebanese patients with T2DM and nephropathy^123,124. The rs1801133 is seen in Kuwaiti exomes (MAF:KWT/1KGP/GME = 0.1810/0.2454/0.2557; AA/AG/GG: 12/81/197). Another MTHFR variant Glu429Ala (rs1801131 T_G AR) in homozygous form has protective effect in Israeli Jews¹²³ and South Indians¹²⁵. The rs1801131 variant is seen in Kuwaiti exomes (MAF: KWT/1KGP/GME = 0.3265/0.2494/0.3353; GG/GT/TT: 31/128/132).

Risk factor by way of inference

AD

0/22/269

0.0378/0.0042/0.0311

9/1.2148