Information

Why is beta thalassemia major not lethal while alpha thalassemia with loss of all 4 genes lethal?


So why is beta thalassemia major with two B0 alleles not fatal in utero (despite the hemoglobin not having any B chains), while alpha thalassemia with deletion of all 4 genes encoding for the alpha chain fatal? Is the alpha chain more important than the beta chain?


This has to do with the fact that fetal hemoglobin (HbF) isn't made of the same chains as adult hemoglobin. The latter comes with 2 alpha chains and 2 beta chains while the main fetal hemoglobin is made of 2 alpha chains and 2 gamma chains. Hence any disease affecting the quality or quantity of beta chains won't have nearly as much impact on a fetus as it does on an adult.

Reference: https://www.uptodate.com/contents/fetal-hemoglobin-hemoglobin-f-in-health-and-disease


In essence, yes, the alpha chain is more important than the beta chain, because there are alternative forms of hemoglobin that can deliver oxygen without beta chains, but the hemoglobin forms without alpha chains cannot.

Hemoglobin has a bunch of different forms, depending on which four globin chains make up the protein. While there are even more, here's an overview of the most important forms:

  • Hemoglobin A is α2β2, this is the normal form, and in adults this makes up 95% of our hemoglobin.
  • Hemoglobin A2 is α2δ2, with 2 delta chains instead of beta chains. It normally makes up about 2-3% of hemoglobin, and its properties are nearly identical to HbA.
  • Hemoglobin F is α2γ2, with 2 gamma chains instead of beta chains. This is the primary form in utero, because it has a higher affinity for oxygen, and thus can extract oxygen from the maternal circulation. It normally decreases after birth, and makes up <1% of adult hemoglobin.
  • Hemoglobin H (β4) and Hemoglobin Bart's (γ4) are defective forms of hemoglobin that occur without alpha chains. Both of these are unstable molecules, and are poor at delivering oxygen because their affinity for oxygen is too high (not allowing it to be released in the tissues).

What you'll notice from the above is that there are functional hemoglobin variants that don't have beta chains, but no functional variants without alpha chains.

If someone has beta thalassemia major, with loss of both β alleles, the body compensates by ramping up production of HbA2 (with delta chains) and HbF (with gamma chains), which compensate for not having HbA. That's not to say that everything is okay… it's still a very serious condition, and usually progresses to death before age 20 if untreated. But, the hemoglobin variants are sufficient enough to allow people to live.

If someone loses all 4 alpha alleles, the only hemoglobin they produce is Hb Bart's, which isn't functional. There are no alternatives to the alpha chain like there are with beta thalassemia, so there's no mechanism to compensate for this loss. Because forming HbF isn't possible without alpha alleles, this condition is fatal in utero.


Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice

In humans, cerebral malaria is a rare but often lethal complication of infection with Plasmodium parasites, the occurrence of which is influenced by complex genetic factors of the host. We used a mouse model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA to study genetic factors regulating appearance of neurological symptoms and associated lethality. In a genome-wide screen of N-ethyl-N-nitrosourea-mutagenized mice derived from C57BL/6J (B6) and 129S1/SvImJ (129) mouse strains, we detected a strong interaction between the genetic backgrounds of these strains, which modulates ECM resistance. We have mapped a major gene locus to central chromosome 4 (log of the odds (LOD) 6.7 79.6–97.3 Mb), which we designate Berr6. B6 alleles at Berr6 are associated with resistance, and are inherited in a co-dominant fashion. In mice heterozygous for Berr6 B6/129 alleles, resistance to ECM is strongly modulated by a second locus, Berr7, that maps to the proximal portion of chromosome 1 (LOD 4.03 41.4 Mb). 129 alleles at Berr7 are associated with ECM resistance in a dosage-dependent fashion. Results are discussed in view of the possible role of this two-locus system in susceptibility to unrelated inflammatory conditions in mice and humans.


Why is beta thalassemia major not lethal while alpha thalassemia with loss of all 4 genes lethal? - Biology

Oman is situated in the South East of the Arabian Peninsula along the East coast of the Arabian Gulf ( Figure 1 ). It has its borders with United Arab Emirates to the North, Saudi Arabia to the West and Yemen to the South West. Oman is the second largest territory in the Arabian Peninsula with an area of 82,000 square miles and a coastline length of 1,300 miles. The native Omani population comprises around 2.2 million inhabitants, and the rate of annual population increase is approximately 25 per 1000. Oman has a young population with nearly half of the population being under 15 years. The Omani population is characterized by a high growth rate, large family size, consanguineous marriages, and the presence of genetic isolates.

Figure 1. Oman is situated in the South East of the Arabian Peninsula along the East coast of the Arabian Gulf.

Clinical genetic services were introduced in the Sultanate of Oman in the past decade and they have become an important component of health care. This greatly facilitated the systematic collection of data on genetic diseases and birth defects in the past few decades. With the inauguration of the National Genetic Center in 2013, the existing clinical genetic services were supplemented by sophisticated genetic laboratory services.

The amount of published data available on genetic disorders in the Sultanate is considerable. There were a few previous attempts to list the genetic diseases reported in Oman 1 – 4 and to link them to specific population groups and geographic locations 5 , 6 , analyze population structure 7 , and to estimate the impact of genetic disorders and birth defects on the community 4 and summarize the genetic services available 8 . The advances in bioinformatics required to annotate human genomic variants and to place them in public data repositories have not kept pace with their discovery. The deposition of such data in the public domain is essential to maximize both their scientific and clinical utility 9 .

Hence, in the current study we present a comprehensive compilation of germline mutations in nuclear genes associated with human disease in the Omani population.

The wealth of genetic variant data in Omani nationals was collected from multiple sources which form a basis for research into genetic conditions reported from Oman. Multiple sources of data were reviewed to form repository of mutations in Omani nationals introduced in this paper. The sources of data included:

(1) 1993� records of patients consulted by clinical geneticists of the Royal Hospital, the largest tertiary hospital in Oman

(2) 2008� publications curated from PUBMED on birth defects and genetic conditions in Omani nationals. The keywords used were: “Oman”, “Genetic disorders”, 𠇋irth defects”, “mutations”

(3) 2012� commercial laboratories referral registry at the Royal Hospital for the samples tested overseas.

(4) The internal genetic variant repository of the National Genetic Center << HTTP://ogvd.net >>

The data presented in this article was manually curated. The OMIM identifiers, Phenotype MIM accession numbers, Phenotype name (OMIM), mutation descriptions, and relevant publications with PMID numbers were all collected from the NCBI database repository. All unavailable through PubMed mutation details were checked with ClinVar, LOVD and CentoMD. The details of unpublished mutations are not included in the present study and feature in Table 2 as “Novel mutations”.

In this study, a wide range of genetic conditions with known mutations collected in Omani nationals were analysed. The disease classifications are comprised of 44 gene variants causing neurodevelopmental disorders, 21 inborn errors of metabolism, 13 endocrinopathies, 15 skeletal dysplasias, nine disorders of the immune system, four hereditary blood disorders as well as other National groups ( Table 1 ).

Table 1. Range of genetic conditions with known mutations in Omani nationals (details presented in Table 2 and Table 3 ).

Range of Genetic Conditions with
known mutations in Omani nationals
Number
of disease
causing genes
Number
of disease
causing
mutations
Novel
Mutations of
known genes
Novel genes
and novel
genetic
mechanisms
Genetic Blood Disorders
             ꂾta-Globin 1 33 2 3
             ਊlpha-Globin 2 22 3 2
             ꃞlta-Globin 1 14 3 0
Other hemolytic and hemorrhagic disorders 3 5 3 2
Neurodevelopmental disorders
        ਌onditions with intellectual disability 20 23 9 7
Primary Microcephaly 5 5 2 2
Epileptic syndromes 2 2 0 1
Neurodegenerative conditions 6 7 1 1
Syndromic ciliopathies 6 7 5 3
Hereditary spastic paraplegias 5 6 4 3
Neuropathies and neuromuscular
disorders
8 13 1 1
Arthrogryposis 3 3 2 2
Inborn errors of metabolism 21 28 21 2
Endocrine disorders 13 28 2 5
Intrahepatic cholestasis and gut anomalies 4 8 3 0
Disorders of the immune system 9 15 3 4
Familial cancers 4 6 1 0
Skeletal dysplasias and osteodysplasias 15 23 6 8
Cardiogenetic conditions 2 2 1 1
Renal disorders and dysplasias 6 13 0 1
Skin, nails, and hair disorders 6 10 0 3
Cutis laxa syndromes 2 7 0 3
Ophthalmological diseases including
blindness
5 8 0 2
Congenital deafness 1 3 0 1
Congenital lipodystrophies 5 5 0 1
Cystic fibrosis 1 4 1 2
Total 156 300 83 58

Extensive genetic studies were performed in Oman for Genetic Blood Disorders and various conditions leading to intellectual disabilities, mental and physical handicap.

In total more than 150 rare genetic disorders were listed in Table 2 and Table 3 with relevant OMIM numbers, PubMed ID (PMID), Gene/Locus name, nucleotide(s) change(s) and the source of the data (PubMed ID Number/ OMIM/ClinVar/LOVD/CentoMD). The names of genetic conditions in Table 2 are stated as found in OMIM “Phenotype-Gene Relationships” table as “Phenotype” arranged in alphabetical order. In Table 3 , we present a separate list of 69 known mutations (11�) that were collected through service provision at the Hemoglobinopathy Laboratory at the National Genetic Center in Oman.

Table 2. List of disease-associated mutations in Omani nationals.

No. Phenotype (OMIM) OMIM PMIM ID Gene/Locus Nucleotide change Source:
Pubmed ID Nos/
Registration at
international
databases
1 Achondroplasia 100800 134934 FGFR3 c.749G>C LOVD
c.1172C>A
2 Adrenal hyperplasia, congenital, due
to 21-hydroxylase deficiency
201910 613815 CYP 21A2 p.I236N 21274396
p.V237E
p.M239K
c. 306T insert,
p.Q318X conv Cyp 21P
to Cyp 21A2
3 Adrenal hyperplasia, congenital, due
to 17-hydroxylase deficiency
202110 609300 CYP17A1 c.287G>A
p.Arg96Gln
24498484
4 Allopecia universalis congenita *203655 602302 HR c. 2776+1, G>A 9736769
c.1022T>A
5 Alport syndrome, autosomal dominant 104199 104200 COL4A3 c.479G>A 14871398
c.232delG
6 Alport syndrome, autosomal recessive 203780 120070 COL4A3 R1215X(CGA>TG 14582039
7 Alport syndrome, X-linked (ATS) 301050 303630 COL 4A5 del exons 7𠄸 and
31�
25333070
15149316
potential duplication
of exons 21 – 30+/-
exon 20
8 Alstrom syndrome *606884 203800 ALMS1 Novel mutation 17594715
9 Amelogenesis imperfecta, type IIA3 *613211 613214 WDR72 c.978T-to-ter 19853237
(V968X)
2857delA
10 Apparent Mineralocorticoid
excess (AME 1)Cortisol 11-beta-
ketoreductase deficiency
*218030 614232 HSD11B2 Exon 1: R74G 15134813
Pdelta1nt
(P75Delta1nt)
Exon2: L114Delta6nt
Exon 5: V322ins9nt
Exon 3 :A221V
11 Arterial tortuosity syndrome 208050 208050 SLC2A10 243C-G 16550171
12 Arthrogryposis, renal dysfunction, and
cholestasis 1
*608552 208085 Vps33B c.350delC 15052268
13 Autoimmune Lymphoproliferative
Syndrome (Type A)
601859 601853 FAS c.232 del G, exon3 8787672
14 Bardet-Biedl Syndrome 9 (BBS9) *615986 615986 PTHB1 IVS 17/IGTA variant 17106446
15 Bardet-Biedl Syndrome 10 (BBS10) *209900 209900 FLJ23560 n.364fsX368 17106446
FLJ 23560
16 Brain Calcifications/Coat’s like
syndrome/Rajab syndrome
*613658 613658 NA Linkage to 2q36.3 19161147
17 Breast cancer 114480 114480 BRCA 1 2080insA 18340530
18 Carbamoylphosphate synthetase I
deficiency
*238970 237300 CPSI c.1590dupT 22106832
19 Carnitinepalmitoyl carboxylase
deficiency
*600650 1p32.3 CPT2 gene detectable mutations
were excluded
ClinVar
20 Central hypoventilation syndrome,
congenital
603851 209880 PHOX2B 5 Alanine Expansions ClinVar
10 Alanine expansions
21 Ceroid lipofuscinosis, neuronal,
2 (CLN2)
*204500 607998 TPP1 positive linkage 17690061
22 Charcot-Marie-Tooth disease, type 4A 214400 214400 GDAP1 Start-codon mutation 22200116
23 Cohen Syndrome (COH 1) *216550 216550 VPS13B 7934G>A 15173253
24 Cystic Fibrosis *219700 7q31.2 CFTR 102T>A+S549R(T>G)] 25829996
10480369
delta F508
F208Del
S549Rdel
25 Cholestasis intrahepatic *243300 243300 ATP8B1 (exon 15) het del CentoMD
15239083
26 Cholestasis, benign recurrent
intrahepatic, 2
605479 605479 ABCB11 c.149G.A LOVD
CentoMD
c.1416T.A
27 Cholestasis, progressive familial
intrahepatic 3
602347 602347 ABCB4 c.2800G>A LOVD
28 Cholestasis, intrahepatic, of
pregnancy, 1
147480 147480 ATP8B1 c.1286A>C LOVD
CentoMD
Novel mutation
Novel mutation
29 Chondrodysplasia, Grebe type (Grebe
Acromesomelic Dysplasia)
*200700 200700 GDF5 Del G1144 16636240
Transition A1137G
30 Chronic granulomatous disease due
to deficiency of NCF1
*233700 233700 NCF1 c.579G>A 24446915
24446915
Novel mutation
31 Chronic Granulomatous Disease,
X-Linked
*306400 306400 CYBB, XK Del gp91-phox gene
(CYBB)
24446915
del McLeod gene (XK)
32 Crigler-Naj ar Syndrome, type II 606785 606785 UGT1A1 c.211G>A 9630669
c.1456T>G
33 Cutis laxa, autosomal recessive,
type IIA (with congenital defect of
glycosulation)
*219200 219200 ATP6V0A2 c.294+1G4A 18157129
c.1929delA
34 Cutis laxa, autosomal recessive,
type IIIB
*614438 614438 PYCR1 356G>A 19648921
566C>T
356G4A
c.356G>A
c.566C>T
35 Deafness, autosomal recessive 1A *220290 2220290 GJB2 S86T 11748849
35delG
167delT
36 Diabetes mellitus, permanent neonatal 606176 606176 ABCC8 c.4480C>T 9769320
37 Dushenne Muscular Dystrophy 320200 320200 DMD Del exon 7 19449031
Dupl exons 55 to 77
c.4996C>T
c.1733_1734delTA
c.1175T > G
c.1647T>G
c.1521_1523delCTT
38 Epiphyseal dysplasia, macrocephaly,
variable CC agenesis, spindle-shaped
fingers, mental retardation
*226900 NA 15q26 Linkage D15S205/
D15S966
11389160
39 Ectodermal dysplasia 1, hypohidrotic,
X-linked (EDA)
305100 305100 ED1 c.G1113A
Gly291Arg
11279189
40 Ectodermal dysplasia 10B,
hypohidrotic/hair/tooth type,
autosomal recessive
224900 224900 EDAR 718delAAA 20979233
41 Enhanced S-cone syndrome (Golden-
Favre syndrome)
*268100 268100 NR2E3 c.1117 A>G 24891813
42 Ellis Van-Creveld *225500 225500 EVC Frameshift in exon 13 17024374
20184732
Novel mutation
43 Epilepsy, progressive myoclonic 2B
(MELF)
254780 254780 NHLRC1 c.468_469delAG 18263761
44 Escobar syndrome *265000 265000 CHRNG �up(3) 16826520
45 Ethyl Malonic Aciduria 608451 608451 ETHE1 c.487C>T Cento MD
14732903
46 Factor X deficiency/Familiar CRM *227600 227600 F10 c.381G>A 12574802
47 Fanconi anemia, complementation
group D1 (FAD1)
605724 605724 BRCA2 9609C>T 22660720
exon 25
48 Fanconi-Bickel Syndrome (GLUT2) 138160 227810 SLC2A2 c.1259G>T 22660720
c.1127T>G
49 Familial Mediterranean fever, AR *608107 247100 MEFV c.442G>C CentoMD,
ClinVar
50 Favism 305900 134700 G6PD c.335A>T 8860013
G6PD Chatham
G6PD A-
2 novel mutations
51 Gastrointestinal defects and
immunodeficiency syndrome
243150 243150 TTC7A Q712X 25534311
52 Geroderma Osteodysplastica
Hereditaria
*231070 231070 SCYL1BP1 C-1_1 :GA>CT 18997784
257delC
53 Geroderma osteodysplastica
Hereditatria
*231070 231070 GORAB 367G-T 19648921
54 Glaucoma 3A, primary open angle,
congenital, juvenile, or adult onset
*231300 231300 CYP1B1 p.G61E 1959767
p.D374N
p.R368H
p.E229K
55 Glycogen Storage Disease II, ACID
ALPHA-GLUCOSIDASE DEFICIENCY
232300 232300 GAA c.2560C>T ClinVar
c.2105G>C
56 Griscelli syndrome, type 2 607624 607624 RAB27A Novel mutation NA
57 Hemolytic uremic syndrome, atypical,
susceptibility to, 3
612923 612923 CFI c.1332A>G CentoMD
58 Hermansky-Pudlak syndrome 2 608233 608233 AP3B1 c.12_13delTA 16537806
8042664
59 Hyperexplexia *149400 149400 GLRA1 c.593G>C 22264702
60 Hemophagocytic lymphohistiocytosis,
familial, 2
*603553 603553 PRF1 c.265C>A 17674359
c. 50delT
c.265>A
.c. 674G>C
c.Del12bP
c.1122G>A/
Del12bP
61 Hyperinsulinemic hypoglycemia,
familial, 1
*256450 256450 ABCC8 c.4480C>T 9769320
25972930
c.96C>A
c.563A>G
c.119T>G
3 novel mutations
62 Hyperinsulinemic Hypoglycemia,
familiar, 5
*147670 609968 INSR Novel mutation NA
63 Hypercholesterolemia, familial *143890 143890 LDLR c.272delG 23162007
24249837
64 Hyperlipoproteinemia, type 1D
(chylomicronemia)
*615947 615947 GPIHBP1 C.149G>A 22106832
65 HYPERPHENYLALANINEM IA BH4-
deficient C, (HPABH4C)
*261630 261630 QDPR Novel mutation NA
66 Hyperoxaluria, primary, type 1 259900 259900 AGXT c.33-34insC CentoMD
21612638
67 Homocystinuria due to MTHFR
deficiency
*236200 236250 MTHFR het 677C-T 15053809
68 Hypoparathyroidism-retardation-
dysmorphism syndrome (Sanhad-
Sakati S)
241410 241410 TBCE c.155-166del12bp 19491227
69 Hypophosphatasia, childhood 241510 241510 ALPL c. 98C>T 25023282
70 Huntington Disease 143100 143100 HTT 41-54 repeats 25689972
71 HUNTINTON-LIKE DISEASE *605613 NIL HIP1R Novel mutation NA
72 Ichthyosis, congenital, autosomal
recessive 1
*242300 242300 TGM1 c.278G>A 23689228
c.396A>H
73 Insensivity to pain, congenital, with
anhydrosis (HSAN IV)
256800 256800 NTRK1 Novel mutation NA
74 Isovaleric acidemia *243500 243500 IVD p.F382fs 22960500
p.R392H
p.R395Q
p.E408K
75 Jouber Syndrome 1 (JBTS1) *213300 213300 INPPSE c.1546C>T in exon 7 19668216
76 Joubert syndrome 5 *610142 610188 CEP 290 c.21G>T exone1 19764032
77 Kindler Syndrome (poikiloderma) *173650 173650 KIND1 R271X 12789646
78 Leprechaunism 147670 246200 INSR Single nucleotide del
in exon 10
OMIM:
147670.0028
79 Leukodystrophy, hypomyelinating, 2
(Pelizaeus-Merzbacher-Like Disease 1)
*608803 608804 GJC2 c.-20+1G>C 23143715
80 LCHAD deficiency 600980 609016 HADHA Novel mutation NA
C Lipodystrophy, congenital
generalized, type 4
*613327 613327 PTRF-Cavin c.160delG 20300641
82 Lipodystrophy, congenital
generalized, type 1 (BSCL1)
608594 608594 AGPAT2 Homozygosity
D9S1818-DS1826
11916958
83 Lipodystrophy, congenital
generalized, type 2 (BSCL2)
606158 269700 SEIPIN Homozygocity 1883-
4136
12116229,
84 Lipodystrophy, familial partial, 2 150330 151660 LAMIN AC Homozygosity 3757 12116229
85 Limb Girdle muscular dystrophy
2BLGMD2B (Miyoshi myopathy)
254130 254130 DYSF C :526C>T 10469840
86 Lissencephaly LIS 4A 300121 300121 DCX exon 5: 11175293
87 Loeys-Dietz syndrome, type 1 609192 609192 TGFBR1 or 2 Positive linkage 16928994
88 Long QT syndrome 1(LQT1) 192500 192500 KCNQ1 1388G>C 15159330
89 MODY type II), Glucokinase related *125851 125891 GCK c.757G>T 24993573
c. 292C>T
90 Mental retardation, autosomal
recessive 43 (MRT 43)
*615817 615817 KIAA1033 c.3056C-G
transversion in exon 29
2149877
91 Mental Retardation, autosomal
recessive
*602810 602810 HIST 3H3 c. R130C 21937992
92 Mental Retardation Autosomal
Recessive, epilepsy, autism
*NA NA DEAF1 c.997+4A>C 26048982
93 Meckel Gruber syndrome (MKS 3) *607361 607361 TMEM67 c. 383-384AC del 16415887
94 Microcephaly with simplified gyral
pattern
*603807 603807 NA Excluded known loci 17975804
95 Microcephaly 3, primary, autosomal
recessive
604804 604804 CDK5RAP2 c. E234X 22887808
96 Microcephaly 5, primary, autosomal
recessive
608716 608716 ASPM c.9153_9154 del ins A 15045028
97 Microcephaly and hypomielination *Omim 179035 NA PYCR2 c.355C>T 25865492
c.751C>T
98 Microcephalic osteodysplastic
primordial dwarfism, type II
*210720 210720 PCNT Maps to 21q22.3 18174396
99 Mucolipidosis IV 252650 252650 MCOLN1 c.1207C>T 15523648
11030752
16287144
Het NM_020533:
c.1208G>T.
100 Mucopolysaccharidosis type IVB
(Morquio)
253010 252010 GLB1 c.1420G>C CentoMD
101 Multiple endocrine neoplasia IIA
(MEN2A)
171400 171400 RET c.1900T>C 8103403
102 Menkes Disease (Kinky Hair Disease) 309400 309400 ATP7A Novel mutation CentoMD
Xq21.1
103 Multiple pterygium syndrome, lethal
type
*100730 253290 CHRNG c.ARG448TER 16826520
104 Myotonic Dystrophy 1 605377 160900 DMPK Expansion, >rpts
1allele
8036515
105 Nephrotic syndrome, type 1 *256300 25630 NPHS1 (121delCT) CentoMD
9660941
c.218C>T
106 Nephrotic syndrome, type 2, steroid
resistant (NPHS2 SRN1)
*600995 600995 NPHS2 c.467Dup/c.709G> CentoMD
15817495
c.709G>C
c.779T>A
107 Noonan syndrome 1 (NS1) 163150 163150 PTPN11 c.218C>T 12161469
108 Niemann-Pick disease, type C1
(NPC1)
*257220 257220 NPC1 c.3362T>G Cento MD
109 Osteogenesis imperfecta, type VIII 610915 610915 LEPRE1 c.2075-1G>A 24498616
LOVD
c.1170+9G>A
110 Osteogenesis imperfecta, type VI 613982 613982 SERPINF1 c.-9+2dup 23054245
111 Osteopetrosis, infantilile malignant *259700 259700 TCIRG1 c.-XY_-YZdel 23685543
112 Orofaciodigital syndrome V *174300 174300 DDX59 c.1600G>A 23972372
113 Paroxysmal nonkinesigenic dyskinesia
(PNKD1)
*118800 118800 MR-1 gene c.20C>T : A7V 16632198
c.26C>T : A9V)
114 Peroxisome biogenesis disorder 1A
(Zellweger)
602136 214100 PEX-1 c.1927_1928dupA. c.
2088A>G
PMCID:
2649967
25407003
115 Pelger-Huet anomaly *169400 169400 LBR del 6 BP in splice site
intron 12
21326950
116 Pheochromosytoma/paraganglioma 4 115310 115310 SDHB c.771dup.A 25034258
15328326
c.574T>C
c.859G>A
117 Pituitary hormone deficiency,
combined, 3
*221750 221750 LHX3 3,088-bp deletion 18407919
118 Pontocerebellar Hypoplasia type III *608027 608027 PCLO nonsense mutation of
PCLO ( piccolo ) gene
25832664
119 Polycystic Kidney and Hepatic
Disease 1
263200 263200 FCYT c.107C>T 11919560
120 Polycystic liver disease 608648 608648 SEC63 Del in promoter
region
24886261
25165181
121 Rabson-Mendenhall syndrome 262190 262190 INSR c.671_685dup CentoMD
22824672
122 Rajab Syndrome *613658 613658 NA linkage D2S351/
D2S2390
19161147
123 Renal tubular acidosis, distal, AR, with
hemolitic anaemia
*611590 611590 SLC4A1 A858D 22126643
A858D/N
124 Retinitis pigmentosa-12, autosomal
recessive
*604210 600105 RABS 1 7 mutations 24512366
125 Retinitis pigmentosa 37 *604485 268100 NR2E3 p.D406G 24891813
126 Rett Syndrome 312750 312750 MECP2 c.880C>T ClinVar
127 Robinow syndrome, autosomal
recessive
*268310 268310 ROR 2 c.1504C>T 10932186
19640924
c.1324C>T
128 Severe combined immunodeficiency,
B cell-negative
179615 601457 RAG1 c.1187G>A ClinVar
129 Spinal Muscular Atrophy (SMN1) 253300 253300 SMN1 del exons 5, 6, 8 15000810
17940251
Del 5q13.2 in exon 7
130 Spastic paraplegia 18, autosomal
recessive (IDMDC)
*611225 611225 ERLIN 2 (D8S1820 and
D8S532)
16636240
131 Spastic paraplegia 20, SPG20 (Troyer
Syndrome)
*275900 275900 SPG 20 c.123X 20437587
132 Spastic paraplegia 35, autosomal
recessive (FAHN) Leukodystrophy,
dysmyelinating, and spastic
paraparesis
612319 612319 FA2H c.235A>C 20104589
133 Spastic paraplegia 54, autosomal
recessive
*615033 615003.0005 DDHD2 1546C-T transition 23176823
134 Spastic paraplegia, ataxia, and
mental retardation
*607565 607565 GRID2 Novel mutation NA
135 Split-hand/foot malformation with long
bone deficiency 3
*612576 612576 BHLHA9 microduplications 22147889
136 Spondylometaepiphyseal dysplasia,
short limb-hand type (SMED-SL)
*271665 271665 DDR2 c.2468_2469del CT 24725993
137 Spondyloepiphyseal dysplasia Omani
type with congenital joint dislocations
*143095 1439095 CHST3 c. 911G>A 15215498
138 Spondylocostal dysostosis 2,
autosomal recessive
605915 608681 MESP2 c.880C>T ClinVar
139 Spinocerebellar ataxia 7
Olivopontocerebellar atrophy III
ADCA type II
164500 164500 ATXN7 Repeat expansion of
ATXN7 gene
ClinVar
140 Schwartz-Jampel syndrome, type 1 *255800 255800 HSPG-2 IVS64DS, A-G, +4
c.1532C>T
11101850
141 Stuve-Wiedemann syndrome/
Schwartz-Jampel type 2 syndrome
601559 601559 LIFR c.653_654insT 14740318
c.643del T
142 Systemic Lupus Erythematosus (SLE),
susceptibility.
*125505 152700 DNASE1L3 G38OR 22019780
143 Thanatophoric Dysplasia type 1 *187600 187600 FGFR-3 R248C 12633765
c.4406A>G
144 Three-M syndrome 1 *273750 273750 CUL c2434C>T 19225462
690 ins C 19877176
145 Three M Syndrome 2 *610991 612921 OBCL1 844ins68 19877176
146 Thrombosis, hyperhomocysteinemic *236200 236200 CBS c.807C>A 16432849
147 Thyroid hormone resistance,
autosomal recessive
190160 274300 TRB2 del in exon10 1991834
Novel mutation NA
148 von Hippel-Lindau syndrome (VHL) *193300 193300 VHL Novel mutation NA

The disorders are listed in alphabetical order along with the mutations detected in Omani patients. Novel genes and/or mutations identified for the first time in Omani nationals are marked by an asterisk (*). Unpublished mutation data referred as “Novel mutations” would be updated following publication, currently source stated as “NA”.

The different mutations reported by the National Genetic Center in patients with Hemoglobinopathies in Oman. Novel mutations are indicated by an asterisk (*) indicated to the left side of the mutation. Mutations are listed in ascending order based on nucleotide position.

For the majority (85%) of rare disorders presented in Table 2 , data was derived from publications. The original mutations identified for the first time in Omani population constitute more than half of rare disease data presented in Table 2 .

Soon after the completion of the Human Genome Project in 2003, it was clear that the genetic data collected until then presented only a glimpse of the complexity of the human genome and the significance of genetic variants in human disease. Since then, genetic researchers have unearthed innumerable variants that are not only individual-specific but also ethnicity-, population- and country-specific. Human genetic variation databases have significant implications for both diagnostic and predictive medicine. Often, the pathogenicity of rare mutations is primarily assessed through multiple reports of occurrence in diseased patients that are documented and routinely updated in mutation databases. Given the fact that gene mutations and their frequencies in many Mendelian disorders differ widely between different ethnic groups, even within a country, national databases are highly valuable resources for studies on disease-gene associations, population diversity and genetic history 10 .

The catalog of Omani mutations presented here will therefore represent a valuable resource that may guide mutation analysis in Omanis suspected of having genetic disease. Unique circumstances in Oman with government-funded comprehensive healthcare throughout the country, and the national coverage for clinical genetics has made the present study possible. Future efforts will be required to extend this database to cover the full spectrum of mutations and population specific variants.

The disease-associated mutation data presented ( Table 1 , Table 2 , Table 3 ) show a considerable proportion of novel disease genes as well as novel genetic variants within the Omani population. This was expected due to the presence of inbred and geographically isolated communities, the practice of consanguineous marriages, all of which have tended to skew the allelic spectrum toward rare and private variants within the Omani population. In addition to this, the list of genetic variants also reveals known mutations that were previously reported in certain non-Omani populations, thereby reflecting the historic genetic admixture that occurred in Oman, along the trade routes of a once powerful Omani empire and its foreign colonies. Many of the mutations reported are unique to the Omani population, suggesting a founder effect.

The interest in genetic testing is growing among physicians aiming to provide better medical care and genetic disease prevention. The data collected largely represent mutations of rare autosomal recessively inherited disorders in Oman. The mutation data in Table 2 can be searched by OMIM number, or by disease name. The names of diseases in Table 2 were chosen as described in OMIM in “Phenotype-Gene Relationships” table as “Phenotype” in order to ease finding specific genetic disorders by name.

The number of collected mutations among different disease groups ( Table 1 ) reflect the frequency of disorders in the Omani population, the burden caused by genetic diseases 4 , and the interests of individual clinicians in genetic testing.

The knowledge of the genetics of Hemoglobin disorders is among the best in Oman due to national preventive programs and research starting from the 1990s. It is not surprising that around a third of all mutations known in Omani population to date are in four genes causing Hemoglobin disorders ( Table 1 , Table 3 ). The birth prevalence of infants with a hemoglobin disorder was recorded as 3.5𠄴.7/1,000 7 , 11 . The frequency of hemoglobin disorders in Oman is among the highest in the world, and may reflect natural selection due to advantage for survival, in the heterozygous state, against malaria. Around 10% of Omani nationals are carriers of the allele for sickle cell anemia, 2𠄳% carry an allele for Beta-thalassemia and 45% are carriers of an alpha-thalassemia allele 12 – 15 .

Genetic disorders causing disabilities and handicap are of great concern. These are different groups of rare disorders leading to intellectual disability or physical handicap requiring detailed clinical classification, genetic testing, research and preventive measures. The high prevalence of birth defects and genetic conditions in Omani communities causes social, psychological and financial difficulties 4 . The development and use of national mutation data is of importance to Omani medical care because it not only allows the genetic burden of disease to be quantified, but also provides diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research 9 . National databases for genetic variants are also significant from the perspective of preventive healthcare. There is a significant correlation between the occurrence of rare genetic variants associated with Mendelian disease and the burden of morbidity from complex diseases within a population. Heterozygous carriers for recessive disease genes do not manifest the recessive disease but may be at risk of developing complex trait conditions with some similarity in phenotype. For example, heterozygote carriers of mutations in the ataxia telangiectasia gene locus are reportedly susceptible to breast cancer 16 , and heterozygote carriers of mutations in the glucocerebrosidase ( GBA ) gene causing Gaucher disease are at an increased risk for Parkinson disease 17 , 18 . Hence, the collection of genetic variant data in national databases will contribute significantly to the prevention of genetic diseases in the population and might greatly impact the management of complex trait diseases in the future. Genetic scientists and international consortiums studying human genetic variation are increasingly interested in dissecting the interplay between genetic makeup and environmental influences on the pattern of diseases worldwide. Current research is expected to create a foundation for the national data online for the benefit of Oman Healthcare.