NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

Dardas, Zain; Fatih, Jawid M.; Jolly, Angad; Dawood, Moez; Du, Haowei; Grochowski, Christopher M.; Jones, Edward G.; Jhangiani, Shalini N.; Wehrens, Xander H. T.; Liu, Pengfei; Bi, Weimin; Boerwinkle, Eric; Posey, Jennifer E.; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.; Coban-Akdemir, Zeynep; Morris, Shaine A.

doi:10.1186/s13073-024-01312-9

Table 1 NODAL variation identified in congenital cardiac laterality defects

From: NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

(a) Single-nucleotide variations and INDELs
ID	Family #	Report	Sex	Ethn.	Inh.	Zyg.	Genomic position	C change	P change	Mut.	vR	tR	gnomAD	CADD_phred	REVEL	ClinVar
CVG005	Family 1	This study	M	NHW	Pat.	Het	10:72201422; A > G	c.2T>C	p.M1T	ms	5	12	.	24.9	0.62	NF
LAT0080	Family 1	This study	M	NHW	Unk	Het	10:72201422; A > G	c.2T>C	p.M1T	ms	5	12	.	24.9	0.62	NF
LAT0022	Family 2	Li&Moh	F	NHW	Pat.	Het	10:72195740; C > A	c.194-1G > T	-	sp	36	65	.	24		LP
LAT0045	Family 2	Li&Moh	F	NHW	Unk	Het	10:72195740; C > A	c.194-1G > T	-	sp				24		LP
LAT1696	Family 3	Li	F	NHW	Unk	Het	10:72195536; G > A	c.397C>T	p.Q133^*	ns	40	81	4.06E-06	28.4	-	P
LAT0123	Family 4	Moh	M	NHA	Unk	Het	10:72195326; C > T	c.607G>A	p.E203K	ms	43	86	0.0004	11.7	0.45	B/LB
LAT1246	Family 5	This study	M	NHW	Pat.	Het	10:72195191; G > A	c.742C>T	p.R248W	ms	87	188	.	32	0.69	US
LAT0191	Family 6	Li&Moh	M	H	Unk	Het	10:72195210–72195233; delins	c.700_723delinsT TGACTTCC	p.R234_P241 delinsLTS	indel	.	.	.	.	.	US
LAT1763	Family 7	Li	F	H	Unk	Het	10:72195210–72195233; delins	c.700_723delinsT TGACTTCC	p.R234_P241 delinsLTS	indel	.	.	.	.	.	US
LAT1763	Family 7	Li	F	H	Mat.	Het	10:72195155; C > T	c.778 G> A	p.G260R	ms	68	126	0.0003	33	0.79	US/LP
CVG0006	Family 8	This study	M	H	AR	Hom	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT0108	Family 9	This study	M	H	AR	Hom	10:72195155; C > T	c.778G>A	p.G260R	ms	142	143	0.0003	33	0.79	US/LP
LAT0265	Family 10	This study	M	H	AR	Hom	10:72195155; C > T	c.778G>A	p.G260R	ms	148	149	0.0003	33	0.79	US/LP
CVG0001	Family 11	This study	M	H	Unk	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT0040	Family 12	Moh	F	H	Mat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT0201	Family 13	Moh	F	H	Mat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	91	185	0.0003	33	0.79	US/LP
LAT0248	Family 14	Moh	M	H	Pat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	49	115	0.0003	33	0.79	US/LP
LAT0658	Family 15	Moh	M	H	Unk	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT0830	Family 16	This study	F	H	Pat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	56	147	0.0003	33	0.79	US/LP
LAT0858	Family 17	Moh	M	H	Unk	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT1016	Family 18	Moh	M	H	de novo	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT0909	Family 19	Moh	M	NHW	de novo	Het	10:72195155; C > T	c.778G>A	p.G260R	ms			0.0003	33	0.79	US/LP
LAT1028	Family 20	Moh	M	H	Pat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	91	173	0.0003	33	0.79	US/LP
LAT1391	Family 21	This study	M	H	Pat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	86	184	0.0003	33	0.79	US/LP
LAT1617	Family 22	This study	M	H	Pat.	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	54	121	0.0003	33	0.79	US/LP
LAT1769	Family 23	This study	M	H	Unk	Het	10:72195155; C > T	c.778G>A	p.G260R	ms	53	108	0.0003	33	0.79	US/LP
LAT0165	Family 24	Moh	M	H	Mat.	Het	10:72195110; G > A	c.823C>T	p.R275C	ms	50	107	4.47E-05	34	0.91	P
CVG0003	Family 25	This study	M	NHW	Pat.	Het	10:72195110; G > A	c.823C>T	p.R275C	ms	50	107	4.47E-05	34	0.91	P
LAT0368	Family 26	Moh	M	NHW	Unk	Het	10:72195083; C > A	c.850G>T	p.V284F	ms			0.00003	24	0.48	NF
LAT0457	Family 27	Moh	M	H	Unk	Het	10:72195041; C > T	c.891 + 1G > A	-	sp			.	33	-	LP
LAT1724	Family 28	This study	M	NHB	Unk	Het	10:72192820; G > A	c.916C>T	p.H306Y	ms	55	100	0.0001	23.3	0.23	LB
LAT0048	Family 29	This study	M	NHW	Pat.	Het	10:72192697; G > A	c.1039C>T	p.L347F	ms	106	208	4.06E-06	31	0.51	NF
(b) Copy number variants (CNV)
ID		Report	Sex	Ethn.	Inh.	Zyg.	Genomic position	Size (bp)	Genes within CNV	*NODAL* exons deletion	SV_freq^a	SV_mut_mech	ClinVar
LAT1415	Family 30	This study	M	NHA	Pat.	Het	10:72204016–72157996; del	46020	EIF4EBP2 & NODAL	1–3	0	AAMR	NF
CVG0007	Family 31	This study	M	NHW	Mat.	Het	10:72189745–72194422; del	4221	NODAL	3	0	AAMR	NF

Li et al. (2019) [15] Eur. J. Hum. Genet., Mohapatra et al. (2009) [13] Hum. Mol. Genet., AAMR Alu-Alu Mediated Rearrangement, B Benign, Ethn. Ethnicity, F Female, fs Frameshift, H Hispanic, Het Heterozygous, Hom Homozygous, indel Insertion-deletion, Inh. Inheritance, LB Likely benign, LP Likely pathogenic, NF Not found, NHA Non-Hispanic Asian, NHB Non-Hispanic black, NHW Non-Hispanic white, ns Nonsense, Mat Maternal, M Male, Mut. Mutation type, ms Missense, P Pathogenic, Pat Paternal, sp Splicing, tR Total read, Unk Unknown, US Unknown significance, vR Variant read, Zyg. Zygosity
^aSV frequencies are reported as the frequency of deletions in gnomAD that completely overlap the deletion CNV found in the proband. Probands with biallelic variants are highlighted in bold

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