INPROGRESS NODAL Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	Congenital heart defects with / without heterotaxy
Inheritance	Autosomal recessive / autosomal dominant / X-linked
Prevalence Possible sources Orphanet Medline Plus Genetics	SCORED AS RARE DUE TO SEVERE HEART DEFECTS +/- HETEROTAXY Phenotypes observed: single ventricle dextrocardia, DORV, AVSD, PS, RAA, PDA, left SVC persisting to coronary sinus, asplenia dextrocardia, single ventricle, DILV, PA, hypoplastic tricuspid valve annulus double outlet right ventricle and transposition of the great arteries. tetralogy of Fallot. conotruncal heart defect. dextrocardia, hypoplastic subpulmonary conus with PS, l-TGA, DORV with posterior main PA, VSD. TGA, VSD, PDA Source:
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD / OMIM	ClinGen - Dosage, little evidence for haploinsufficiency (2013). GenCC - Strong for AD visceral heterotaxy (INVITAE). BabySeq - none. HGMD curated LOF variants below
Clinical Validity Scoring Notes and points	NODAL IS LOF CONSTRAINED, LOEUF 0.31. Note there is an alternate start codon in exon 2 that is used by transcripts NM_001329906 EXON 1 *c.123_142dup20 p.(Tyr48Trpfs5) - NMD+, located in exon 1, absent gnomAD. PMID: 30293987 - Identified in family 195 and 835. Per supplement, in family 195, the variant was found in proband with functional single ventricle, segregated in affected sib with a VSD, but was inherited from the unaffected father. 1 POINT (downgrading due to reduced penetrance) In family 835, the variant was found in proband with dextrocardia, DORV, AVSD, PS, RAA, PDA, left SVC persisting to coronary sinus, asplenia and was inherited from father with “hole in heart”. 2 POINTS Being generous, counting 2 affected segregations across both families. REDUCED PENETRANCE c.182T>A p.L61Q - absent gnomad REVEL Score: 0.690. PMID: 22352765 - requested article, per HGMD found in patient with Congenital heart disease EXON 2 c.194-1G>T - absent gnomad v2, NMD+ variant, located in intron 1. PMID: 19064609 (2009) - found in one individual per table 1. Table 2, reported in a patient with dextrocardia, single ventricle, DILV, PA, hypoplastic tricuspid valve annulus. PMID: 30622330 - overlaping authors with PMID: 19064609, same proband reported LAT0022. Variant inherited from unaffected father, and shared by an affected paternal aunt. 1 POINT (DOWNGRADE FOR REDUCED PENETRANCE)** c.397C>T p.Q133* (Cardiac defects) - Exon 2. Path by Invitae, absent gnomAD v2, NMD+. PMID: 29368431 reported in patient 9 with double outlet right ventricle and transposition of the great arteries. Also had a variant in CITED2 which is also associated with congenital heart disease (moderate curations by LMM and Ambry), but this variant is present in 54/58840 admixed american alleles in gnomAD. 2 POINT c.692G>A p.W231* - EXON 2. 3 alleles gnomAD v4, NMD+. PMID: 34328347 Found in a cohort of patients with tetralogy of Fallot. 2 POINTS *c.700_707delAGGCACCG p.(Arg234Serfs41) - absent gnomAD NMD +. PMID: 30622330 - Found in patient LAT1763M with conotruncal heart defect. PER TEXT INHERITED FROM UNAFFECTED PARENT REDUCED PENETRANCE, DOWNGRADE 1 POINTS Also found in LAT0191 with a complex defect. See table 2; but this individual is also reported in PMID: 19064609 WITH A different in frame variant, so I am going to score conservatively under taht variant below (see c.700_723delinsTTGACTTCC) c.891+1 G>A - located in last intron at splice donor site, unclear if NMD will occur. Absent gnomAD. P/LP by Invitae. PMID: 19064609 (2009) - reported in patient LAT0457 with dextrocardia, hypoplastic subpulmonary conus with PS, l-TGA, DORV with posterior main PA, VSD. 1 POINT c.700_723delinsTTGACTTCC p.(Arg234_Pro241delinsLeuThrSer) - absent gnomAD, non-NMD variant. PMID: 19064609 in patient LAT0191 d-TGA, single ventricle, DILV, PA, ASD, intra-atrial re-entrant tachycardia However, this is the same patient ID reported in PMID: 30622330 and variant is descibed as a FS there. In PMID: 19553149, - per HGMD confirmed by personal communication, variant is called delSJ. Variant has 15% activity of WT based on luciferase assay. Scoring 0.5 point for non-NMD variant, but in herited from unaffected parent per text, -0.5 point, scoring just the 0.5 point for functional. EXON 3 c.892-1G>C** - last intron acceptor site, absent gnomAD, unclear if NMD will occur. PMID: 19933292 - reported in proband of family 6 with transposition of the great arteries. Also had a variant in CFC1, which also is scored as strong for heterotaxy in GenCC by Invitae. No points due to potential alternate cause. c.919C>T p.R307* - NMD-, absent gnomAD. PMID: 30293987 per supplement, in family 3766, found in proband with TGA, VSD, PDA, but inherited from mother who only had a heart murmur. 1 POINT REDUCED PENETRANCE LOF citations from Invitae PMID: 19064609, 19933292 EXPERIMENTAL PMID: 12730124 - In mice “ It is well established that Nodal heterozy-gotes are normal and are born in expected Mendelian ratios” . However double het mice with Zic3 / NODAL haploinsufficient are born in reduced numbers. PMID: 19064609 - the missense variants identified in patients with were tested using a luciferase reporter assay and found decrease signaling. However, many of the probands reported had the Gly260Arg variant which has a relatively high MAF in gnomAD (0.2%, 78/35440 Admixed american gAD v4. Variants were shown to have found decreased expression on Western blot in P19 cells, mislocalization of phospho-Smad2 in cells transfected with NODAL variant constructs
Clinical Validity Points Total	11.5 Source:
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Moderate Source:
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function See variants scored under clinical validity. However, unclear if truncations in exon 1 cause disease; there is an alternate start in exon 2 where most variants are located.
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
Clinical Features	Sources:
HPO Terms https://hpo.jax.org/app/
Gene SOPs & Notes	LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
Case ID, Curator name, Date, Jira ticket link

INPROGRESS NODAL Gene Curation

Congenital heart defects with / without heterotaxy