Exome sequencing for diagnosis of congenital hemolytic anemia

Mansour-Hendili, Lamisse; Aissat, Abdelrazak; Badaoui, Bouchra; Sakka, Mehdi; Gameiro, Christine; Ortonne, Valérie; Wagner-Ballon, Orianne; Pissard, Serge; Picard, Véronique; Ghazal, Khaldoun; Bahuau, Michel; Guitton, Corinne; Mansour, Ziad; Duplan, Mylène; Petit, Arnaud; Costedoat-Chalumeau, Nathalie; Michel, Marc; Bartolucci, Pablo; Moutereau, Stéphane; Funalot, Benoît; Galactéros, Frédéric

doi:10.1186/s13023-020-01425-5

Orphanet Journal of Rare Diseases

Table 2 Genetic results of UH patients

From: Exome sequencing for diagnosis of congenital hemolytic anemia

Patient ID	Gene name	Transcript	Nucleotide change	AA change	zygosity	references	gnomAD allele frequency	Polyphen-2	Mutation taster	MaxEnt Scan	CADD score	ACMG class
P21	SPTA1	NM_003126	c.6600 + 5G > T		het	no	0	NA	NA	−62.5%	18.74	VUS
	SPTA1	NM_003126	c.6531-12C > T		het	Alpha-Lely polymorphism rs28525570	25%
P22	SPTA1	NM_003126	C.2898G > A	p.(=)	het	no	0	NA	NA	−29.3%	14.2	VUS
	SPTA1	NM_003126	c.6531-12C > T		het	Alpha-Lely polymorphism rs28525570	25%
P23	ALAS2	NM_000032	c.-258C > G		het	Bekri et al 2003 rs140772352	0.54%	NA	NA	NA		VUS
P24	TRPV4	NM_021625	c.1913C > T	p.P638L	hom	No rs35058636	0.03% (no homozygotes)	B	DC	No effect		VUS
	ADAR	NM_001111	c.1586C > T	p.P529L	het	no	0	PD	DC	No effect		VUS
P25	SEC23B	NM_001172745	c.40C > T	p.R14W	het	Russo et al 2011 rs121918222	0.022%	PossD	DC	No effect		P
	SEC23B	NM_001172745	c.325G > A	p.E109K	het	Russo et al 2011 Rs121918221	0.023%	PD	DC	No effect		P
P26	HAMP	NM_021175	c.49_54del	p.L17_L18del	het	no	0	NA	NA	No effect		VUS
	HFE	NM_000410	c.845G > A	p.C282Y	het	rs1800562	3.37%	PD	P	No effect		P
	CD46	NM_172359	c.402 T > G	p.I134M	het	no	0	PossD	P	No effect		VUS
P27	CFH	NM_00186	c.2850G > T	p.Q950H	het	Mohlin et al 2015 rs149474608	0.39%	B	P	No effect		LB
P28	SEC23B	NM_001172745	c.1276G > A	p.V426I	het	Schwartz et al 2009 rs41309927	4.3%	B	P	No effect		VUS
	CDAN1	NM_138477	c.256C > T	p.P86S	het	No rs543791953	0.052%	B	P	No effect		VUS
P29	SPTA1	NM_003126	c.1688G > A	p.R563Q	het	No rs202243588	0.11%	PD	DC	Possible new acceptor site	25.1	VUS
	HBB	NM_000518	c.20A > T	p.E7V	het	Yes coding for HbS rs334	0.44%	B	P		13.8	P
	SPTA1	NM_003126	c.6531-12C > T		het	Alpha-Lely polymorphism rs28525570
P30	PIEZO1	NM_001142864	c.1126C > G	p.P376A	het	no	0	B	P	Possible new acceptor site		VUS
P31	KCNN4	NM_002250	c.1055G > A	p.R352H	het	Rappetti Mauss et al 2015 rs774455945	0	PossD	DC	No effect		P
	PIEZO1	NM_001142864	c.3629C > T	p.A1210V	het	No rs761971227	0.006%	B	DC	No effect		LP
	PIEZO1	NM_001142864	c.3629C > T	p.A1210V	absence
P32	SPTB	NM_001024858	c.[6706C > A;6737C > T]	p.[L2236M;A2246V]	Het in cis	no	0	B/PD	DC/P	No effect		VUS
	HBB	NM_000518	c.20A > T	p.E7V	het	Yes coding for HbS rs334	0.44%	B	P		13.8	P
P33	G6PD	NM_000402	c.538G > A	p.V180I	het	no	0	PossD	DC	No effect		VUS
	SPTB	NM_001024858	c.6271C > A	p.P2091T	het	No rs372733273	0.0065%	B	DC	no effect		VUS
P34	HFE	NM_000410	c.187C > G	p.H63D	hom	Kaczoeowska-Hac et al 2016 rs1799945	10.83%	B	P	No effect		LB
	ABCG8	NM_022437	c.-27G > A		het	no	0	NA	NA	NA		VUS
	ADAMTS13	NM_139025	c.119C > G	p.A40G	het	No rs782213090	0.00041%	B	P			VUS
	ADAMTS13	NM_139025	c.4007G > A	p.R1336Q	het	No No rs	0.0012%	PD	P			VUS
P35	SH2B3	NM_005475	c.1A > G	p.0?	het	no	0	NA	NA	No effect		LP
	SCN9A	NM_002977	c.2938G > T	p.A980S	het	no	0	PossD	DC	No effect		VUS
P36	SPTA1	NM_003126	c.6672A > C	p.E2224D	hom	No Rs142775522	1.5% no homozygotes	PD	DC	No effect	22.3	VUS
	SLC4A1	NM_000342	c.1199_1225del	p.A400_A408del	het	Wilder et al 2009 rs769664228	0.0047%	PD	DC			LP
	PIEZO1	NM_001142864	c.1369C > T	p.R457C	het	Russo et al 2018	0	PD	DC	No effect		LP
	G6PD	NM_000402	c.292G > A	p.V98M	het	Vulliamy et al 1988 rs1050828	1.15%					LP
	HBB	NM_000518	c.20A > T	p.E7V	het	Yes coding for HbS rs334	0.44%	B	P		13.8	P
P37	SPTA1	NM_003126	c.3291G > A	p.W1097*	het	no	0	NA	NA	NA	42	LP
	SPTA1	NM_003126	c.6531-12C > T		het	Alpha-Lely polymorphism rs28525570
	HFE	NM_000410	c.187C > G	p.H63D	hom	Kaczoeowska-Hac et al 2016 rs1799945	10.83%	B	P	No effect		LB
P38	CFH	NM_00186	c.157C > T	p.R53C	het	Servais et al 2012 rs757785149	0.0014%	PD	DC	No effect		LP
	PIEZO1	NM_001142864	c.4246G > A	p.G1416R	het	No rs771605269	0.00033%	PD	DC	New cryptic acceptor site		VUS
P39	SPTA1	NM_003126	c.779 T > C	p.L260P	het	Marchesi et al 1987 Rs121918634	0.017% (Afr)	PD	DC	No effect		LP
	SPTA1	NM_003126	c.6531-12C > T		het	Alpha-Lely polymorphism rs28525570
P40	ATP11C	NM_173694	c.2434C > T	p.P812S	hem	no	0.00055% no hemizygous	PD	DC	No effect		VUS
	ANK1	NM_020476	c.4558G > C	p.E1520Q	het	no	0.0021%	B	DC	No effect	26	VUS

Table 2 Legend: Variants description and classification according to ACMG guidelines as benign likely benign (LB), variant of uncertain significance. (VUS), likely pathogenic (LP) or pathogenic (P). In silico study of missense variations was assessed thanks to Polyphen-2, Mutation taster andCADD score algorithm. HGMD professional and pubmed web interface were used to check for variants description in litterature. Abbreviations: het: heterozygous state; hom: homozygous state; hem: hemizygous state; F: female; M: male; HS: hereditary spherocytosis; gnomAD: genome agregation database https://gnomad.broadinstitute.org; ND: not done; NA: not applicable; DC: disease causing; P: polymorphism; PD: probably damaging; PossD: possibly damaging; B: benign.

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ISSN: 1750-1172

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