Spectrum of genetic variants associated with maple syrup urine disease in the Middle East, North Africa, and Türkiye (MENAT): a systematic review

Younes, Salma; Elkahlout, Razan; Kilani, Houda; Okashah, Sarah; Sharshani, Hussain Al; Rezoug, Zoulikha; Zayed, Hatem; Al-Dewik, Nader

doi:10.1186/s12920-025-02083-x

Table 2 Variants captured among MSUD patients in the MENAT region

From: Spectrum of genetic variants associated with maple syrup urine disease in the Middle East, North Africa, and Türkiye (MENAT): a systematic review

Gene	Nucleotide change	Protein change	Zygosity	Variant type	Phenotype	Total number of patients screened	Number of patients reported with the variant	Country of origin	Consanguinity	Ref.
BCKDHA	c.488_1167+3del	p.Val163Glyfs*6	HO	Frameshift	Intermediate	5	1	Lebanon	Yes	[33]
BCKDHA	c.409G>A†	p.Glu137Lys	HO	Missense	NR	52	1	KSA	Yes	[9]
BCKDHA	c.660_663delGTAC	p.Tyr221Glnfs108	HO	Frameshift	Severe	52	1	KSA	Yes	[9]
BCKDHA	c.809G>A†	p.Ala270Thr	HO	Missense	Intermediate	52	2	KSA	Yes	[9]
BCKDHA	c.896A>C†	p.Asp299Ala	HO	Missense	Severe	52	1	KSA	Yes	[9]
BCKDHA	c.1270C>T	p.Gln424Ter	HO	Nonsense	Severe	52	1	KSA	Yes	[9]
BCKDHA	c.143delT	p.Leu48ArgfsX14	HO	Frameshift	Severe	20, 40	1, 1	Iran, Iran	Yes, Yes	[34, 35]
BCKDHA	c.(375+1376-1)(884+1885-1)	Splice	HO	Deletion	Severe	20	1	Iran	Yes	[34]
BCKDHA	c.375+648_484+520del	p.Gly126ValfsTer3	HO	Frameshift	Severe	1	1	Kurdish Iraq	Yes	[3]
BCKDHA	c.702delT	p.Tyr235ThrfsX94	HO	Frameshift	Severe	40, 20	1, 1	Iran, Iran	Yes, Yes	[34, 35]
BCKDHA	c.731G>A†	p.Gly244Glu	HO	Missense	Severe	40, 20	1, 1	Iran, Iran	Yes, Yes	[34, 35]
BCKDHA	c.1167+1G>T	Splice	HO	Splice site	Severe	40, 20	1, 1	Iran, Iran	Yes, Yes	[34, 35]
BCKDHA	c.(375+1_376–1)_(884+1_885–1)del	Splice	CH	Deletion	Severe	40	1	Iran	Yes	[35]
BCKDHA	c.355–356Ins7nt	p.D355Dfs	HO	Frameshift	Severe	40	1	Iran	Yes	[35]
BCKDHA	c.703delT	Splice	HO	Deletion	Severe	40	1	Iran	Yes	[35]
BCKDHA	c.773G>A†	p.Cys258Tyr	HO	Missense	Severe	12, 19	3, 1	Turkey, Turkey	-, Yes	[12, 43]
BCKDHA	c.373C>G‡	p.Gln125Glu	HO	Missense	Severe	12, 19	1, 1	Turkey, Turkey	-, Yes	[12, 43]
BCKDHA	c.783G>A+784C>A	p.Cys258Ter	CH	Nonsense	Severe	19	1	Turkey	No	[43]
BCKDHA	c.919G>A†	p.Arg297His	CH	Missense	Mild	19, 15	1, 1	Turkey, Turkey	No, Yes	[36, 43]
BCKDHA	c.982G>A†	p.Ala328Thr	HO	Missense	Mild	19, 15	1, 1	Turkey, Turkey	Yes, Yes	[36, 43]
BCKDHB	c.1006G>A*	p.Gly336Ser	HO	Missense	Severe	52	3	KSA	Yes	[9]
BCKDHA	c.908_909delTG	p.Phe304Cysfs*36	HO	Frameshift	Severe	9	1	Jordan	Yes	[37]
BCKDHA	c.512_512delT	p.Leu171Argfs*159	CH	Frameshift	Severe	33	1	Egypt	-	[38]
BCKDHA	c.947_956delGGGCTGTGGC	p.Arg316Glnfs*11	CH	Frameshift	Severe	33	1	Egypt	-	[38]
BCKDHA	c.859_866delCGAGGCCC	p.Gly288Valfs*11	CH	Frameshift	Severe	33	1	Egypt	-	[38]
BCKDHA	c.205C>T	p.Gln69Ter	HO	Nonsense	Severe	19	1	Turkey	No	[43]
BCKDHB	c.716A>G†	p.Glu239Gly	HO	Missense	Severe	3	2	Tunisia	Yes	[39]
BCKDHB	c.(343+1_344–1)_(742+1_743–1)del	Splice	CH	Deletion	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.92_102del	p.Arg31Glnfs*16	HO	Frameshift	Intermediate	5	1	Lebanon	Yes	[33]
BCKDHB	c.197G>C‡	p.Gly66Arg	HO	Missense	Severe	52	3	KSA	Yes	[9]
BCKDHB	c.286delGAA	p.Glu96del	HO	Deletion	Severe	52	1	KSA	Yes	[9]
BCKDHB	c.1004G>A‡	p.Gly335Asp	HO	Missense	Severe	52	3	KSA	Yes	[9]
BCKDHB	c.1145T>C†	p.Cys382Ser	HO	Missense	Severe	52	1	KSA	Yes	[9]
BCKDHB	c.833_834insCAC	p. Gly278_Thr279insThr	HO	Insertion	Severe	40, 21	1, 1	Iran, Iran	Yes, Yes	[35] [41]
BCKDHB	c.834_836dupCAC	Splice	HO	Duplication	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.484A>G†	p.Asn162Asp	HO	Missense	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.357delT	p.Leu119>Leufs	HO	Frameshift	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.272C>T†	p.Ala91Val	HO	Missense	Severe	19	2	Turkey	Yes	[43]
BCKDHB	c.1149T>A	p.Tyr383Stop	HO	Nonsense	Severe	19, 19	3, 2	Turkey, Turkey	Yes, -	[40, 43]
BCKDHA	c.116C>A*	p.Pro39His	HO	Missense	Severe	19	1	Turkey	-	[40]
BCKDHB	c.688G>T	p.Glu230Ter	HO	Nonsense	Severe	19	1	Turkey	Yes	[43]
BCKDHB	c.1015T>C†	p.Ser339Leu	HO	Missense	Severe	19	1	Turkey	Yes	[43]
BCKDHB	c.(274+-1_275-1)_(343+-1_344-1)del	Splice	CH	Deletion	Severe	21, 40	1, 1	Iran, Iran	Yes, Yes	[35, 41]
BCKDHB	c.1091A>G†	p.Asp364Gly	HO	Missense	Moderate	33	4	Egypt	-	[38]
BCKDHB	c.806G>A†	p.Gly269Glu	HO	Missense	Moderate	33	1	Egypt	-	[38]
BCKDHB	c.287_287delA	p.Asp97Metfas*133	HO	Frameshift	Moderate	33	2	Egypt	-	[38]
BCKDHB	c.908_909insA	p.Asp303Glufs*15	HO	Frameshift	Severe	33	2	Egypt	-	[38]
DBT	c.224G>A†	p.Gly75Glu	HO	Missense	Severe	5	2	Lebanon	Yes	[33]
DBT	c.1195T>C†	p.Ser399Pro	HO	Missense	Severe	52	1	KSA	Yes	[9]
DBT	c.1281+3A>G	Splice	CH	Splice site	NR	52	2	KSA	Yes	[9]
DBT	c.562G>T	p.Gly188Trp	HO	Missense	Severe	40	1	Iran	Yes	[35]
DBT	c.(363delCT)+(1238T>C)†	p.(Leu121Leufs) + (Ile413Thr)	CH	Frameshift	Severe	40	1	Iran	Yes	[35]
DBT	c.(433+1_434–1)_(939+1_940–1)del	Splice	CH	Deletion	Severe	40	1	Iran	Yes	[35]
DBT	c.1174A>C ‡	p.Thr392Pro	HO	Missense	Severe	10, 40	1, 1	Iran, Iran	Yes, Yes	[35, 45]
DBT	c.85_86insAACG	Splice	HO	Insertion	Severe	40	1	Iran	Yes	[35]
DBT	IVS3-1G>A	Splice	HO	Splice site	Severe	12, 19	1, 1	Turkey, Turkey	-, Yes	[12, 43]
DBT	c.788T>G†	p.Met263Arg	HO	Missense	Severe	19	2	Turkey	Yes	[43]
DBT	c.940-1G>A	p.Ala314-Lys339del	HO	Deletion	Severe	32, 19, 19	1, 1, 1	Turkey, Turkey, Turkey	Yes, Yes, -	[42, 43] [40]
DBT	c.1333_1336delAATG	p.Asn445Ter	HO	Nonsense	Severe	3	1	Tunisia	Yes	[39]
DBT	c.787A>T†	p.Met263Leu	HO	Missense	Severe	9	2	Jordan	Yes	[37]
DBT	c.1202T>C	p.Ile401Thr	HO	Missense	Severe	19	1	Turkey	Yes	[43]
DBT	c.61delC	p.Arg21Alafs12	HO	Frameshift	NR	52	2	KSA	Yes	[9]
DBT	c.939-2A>G	Splice	HO	Splice site	Severe	52	1	KSA	Yes	[9]
DBT	IVS8-1G>A+c.1202T>C	Splice	CH	Splice site	Severe	19	1	Turkey	No	[43]
DBT	c.1291C>T*	p.Arg431Stop	HO	Nonsense	NR	33, 40	5, 1	Egypt, Iran	- , Yes	[38] [35]
BCKDHA	c.1312T>A*	p.Tyr438Asn	HO	Missense	NR	33	4	Egypt	-	[38]
PPM1K	c.1A>G	N/A	HO	Start-loss	NR	1	1	Turkey	Yes	[44]
DBT	c.241_242delGT	p.Val81Ter	CH	Nonsense	Severe	33	1	Egypt	-	[38]
BCKDHB	c.1A>T	p.Met1?*	HO	Nonsense	Severe	52	3	KSA	Yes	[9]
BCKDHA	c.288+1G>A*	Splice	HO	Splice site	Severe	40, 20	2, 1	Iran, Iran	Yes, Yes	[35] [34]
BCKDHB	c.331C>T*	p.Arg111Ter	HO	Nonsense	Severe	19	1	Turkey	Yes	[43]
BCKDHA	c.347A>G	p.Asp116Gly	HO	Missense	Severe	52	1	KSA	Yes	[9]
BCKDHB	c.410C>T*	p.Ala137Val	HO	Missense	NR	34, 40	1, 1	Egypt, Iran	-, Yes	[35, 38]
BCKDHA	c.452C>T*	p.Thr151Met	HO	Missense	Severe	40, 19	1, 1	Iran, Turkey	Yes, -	[35] [40]
DBT	c.74delAT	p.C26Wfs12	HO	Frameshift	NR	52	1	KSA	Yes	[9]
DBT	c.137A>G	p.Lys46Arg	HO	Missense	Severe	52	3	KSA	Yes	[9]
BCKDHB	c.477+1G>A*	Splice	HO	Splice site	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.502C>T*	p.Arg168Cys	HO	Missense	Severe	52	2	KSA	Yes	[9]
BCKDHB	c.547C>T*†	p.Arg183Trp	HO	Missense	Severe	19	1	Turkey	Yes	[43]
BCKDHB	c.564T>A	p.Cys188Stop	HO	Nonsense	Severe	19	1	Turkey	Yes	[43]
DBT	c.30G>A	p.Try10Stop	HO	Nonsense	NR	34	1	Egypt	-	[38]
BCKDHB	c.574G>A	p.Gly192Arg	HO	Missense	Severe	52	1	KSA	Yes	[9]
BCKDHB	c.599C>T*	p.Pro200Leu	HO	Missense	Severe	40	1	Iran	Yes	[35]
BCKDHB	c.633+1G>A*	Splice	HO	Splice site	Severe	40, 21	2, 1	Iran, Iran	Yes, Yes	[35] [41]
BCKDHA	IVS6-1G>C	Splice	HO	Splice site	Severe	19	1	Turkey	Yes	[43]
BCKDHA	c.647-1G>C*	Splice	CH	Splice site	NR	52, 9	1, 3	KSA, Jordan	Yes, No	[9] [37]
DBT	c.670G>T	p.Glu224Stop	HO	Nonsense	NR	33	4	Egypt	-	[38]
BCKDHB	c.752T>C	p.Val251Ala	HO	Missense	Severe	19, 19	1, 1	Turkey, Turkey	Yes, -	[40, 43]
BCKDHA	c.757G>A*	p.Ala253Thr	HO	Missense	Severe	19	1	Turkey	Yes	[43]
BCKDHB	c.665A>G	p.Lys222Arg	HO	Missense	Severe	19, 19	1, 1	Turkey, Turkey	Yes, -	[40, 43]
BCKDHB	c.817A>C	p.Thr273Pro	HO	Missense	Intermediate	52	8	KSA	Yes	[9]
BCKDHB	c.853C>T*	p.Arg285Stop	HO	Nonsense	NR	52, 34, 19, 40, 19	2, 1, 2, 1, 1	KSA, Egypt, Turkey, Iran, Turkey	Yes, - , Yes, Yes, -	[9, 38] [35, 40, 43]
BCKDHA	c.859C>T*	p.Arg287Stop	HO	Nonsense	NR	34, 19, 19	1, 1, 1	Egypt, Turkey, Turkey	-, -, Yes	[38, 40] [43]
BCKDHA	c.868G>A*	p.Gly290Arg	HO	Missense	Severe	19, 19	1, 1	Turkey, Turkey	-, Yes	[40, 43]
BCKDHB	c.508G>T*	p.Arg170Cys	HO	Missense	Severe	40, 21	3, 5	Iran, Iran	Yes, Yes	[35, 41]
BCKDHA	c.890G>A	p.Arg297His	HO	Missense	Severe	40, 9	1, 2	Iran, Jordan	Yes, Yes	[35, 37]
BCKDHA	c.905A>C*	p.Asp302A1a	HO	Missense	Severe	52	4	KSA	Yes	[9]
BCKDHB	c.730T>C	p.Tyr244His	HO	Missense	Severe	40	1	Iran	Yes	[35]
BCKDHA	c.940C>T*	p.Arg314Ter	HO	Missense	Severe	52	1	KSA	Yes	[9]
BCKDHB	c.970C>T*	p.Arg324Stop	HO	Nonsense	NR	34	2	Egypt	-	[38]
BCKDHB	c.988G>A*	p.Glu330Lys	HO	Missense	Severe	40, 21	5, 4	Iran, Iran	Yes, Yes	[35, 41]
BCKDHB	c.995C>T	p.Pro332Leu	HO	Missense	NR	34	4	Egypt	-	[38]
BCKDHA	c.1251delC	p.Aal418Profs*67	HO	Frameshift	NR	9	1	Jordan	Yes	[37]
DBT	c.1057A>T,c.1150A>G*	p.Gly353Ser, p.Gly384Ser	CH	Missense	NR	9	1	Jordan	Yes	[37]
BCKDHA	IVS8-2A>G	Splice	HO	Splice site	Severe	19	1	Turkey	Yes	[43]

Homozygous mutations (Zygosity HO) denote instances where both alleles are identical, while Compound Heterozygous mutations (Zygosity CH) involve different alleles. The presence (Consanguinity Yes) or absence (Consanguinity No) of consanguineous relationships is indicated. PolyPhen (Probably damaging†): Predicted to be damaging to protein function. PolyPhen (Possibly damaging ‡): Predicted to possibly be damaging to protein function. Variants marked with an asterisk (*) are considered shared if reported in real patients, published articles, submitted to ClinVar, or present in the population database (gnomAD). Data about shared variants, including their reported populations and allele frequencies, are provided in Table S3 and Fig. 3. Variants without an asterisk are deemed unique to the MENAT region if absent from the mentioned databases and are depicted in Fig. 3. The abbreviation NR denotes Not Reported or Not Applicable

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