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Fetal anomalies v6.138 CELSR3 Achchuthan Shanmugasundram edited their review of gene: CELSR3: Added comment: PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans.

Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 26 February 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype. This gene is also rated green on the Fetal anomalies panel of PanelApp Australia.; Changed rating: GREEN; Changed publications to: 38429302; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, congenital anomaly of kidney and urinary tract, MONDO:0019719; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.112 DISP1 Ida Ertmanska changed review comment from: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Fetal anomalies v6.112 DISP1 Ida Ertmanska commented on gene: DISP1: Comment on mode of inheritance: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition. Gene tagged for expert review to decide the appropriate MOI.
Fetal anomalies v6.112 DISP1 Ida Ertmanska changed review comment from: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. One these cases was a foetus reported with extensive posterior Periventricular nodular heterotopia (PMID:33639934).

In addition, PMID:30266093 (2018) reported a foetus with abnormalities identified via ultrasound and with compound heterozygous LAMC3 variants

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene is also green with biallelic MOI on the Fetal anomalies panel of PanelApp Australia (https://panelapp-aus.org/panels/3763/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).

This gene should therefore remain green with Biallelic MOI on this panel.; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. One these cases was a foetus reported with extensive posterior Periventricular nodular heterotopia (PMID:33639934).

In addition, PMID:30266093 (2018) reported a foetus with abnormalities identified via ultrasound and with compound heterozygous LAMC3 variants

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene is also green with biallelic MOI on the Fetal anomalies panel of PanelApp Australia (https://panelapp-aus.org/panels/3763/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Fetal anomalies v6.105 PTBP1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Skeletal anomalies were seen in 24 (89%), with the most prominent abnormalities comprising shortening and dysplasia of long bones and phalanges. Radiographic features included brachymetacarpia, brachymetatarsia, brachydactyly, brachytelephalangy, brachymesophalangy, and rhizomelia. Advanced bone maturation, cone-shaped epiphyses, and other features such as vertebral dysplasia were also observed.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Prenatal ultrasound was abnormal in thirteen (48%), revealing short femora (5/13, 38%), IUGR (31%), hydramnios (2/13, 15%), increased nuchal translucency (15%), asymmetry of heart cavities (1/13, 8%), and bilateral hydronephrosis (8%). It led to the diagnosis of skeletal dysplasia in two.
Fetal anomalies v6.101 DISP1 Ida Ertmanska changed review comment from: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Fetal anomalies v6.97 LINC01082 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

There is only 1 individual with ACDMPV where only LINC01082 has been deleted, without affecting FOXF1 or LINC01081 (PMID: 24842713). At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01082 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01082 Ida Ertmanska commented on gene: LINC01082: Comment on list classification: Genes in the FOXF1 enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). There is only 1 individual with ACDMPV where only LINC01082 has been deleted, without affecting FOXF1 or LINC01081 (PMID: 24842713). At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Hence, the testing region should be expanded to include the enhancer.
The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.90 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Fetal anomalies.
Fetal anomalies v6.82 ITGAV Arina Puzriakova changed review comment from: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; to: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.

Previously curated as Amber as only one family had fetal cases reported on; however as noted in Natalie Canham review, all affected individuals have brain anomalies which could be detected prenatally. Therefore this gene can be rated Green.
Fetal anomalies v5.96 C1orf127 Julia Baptista gene: C1orf127 was added
gene: C1orf127 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy
Review for gene: C1orf127 was set to GREEN
Added comment: OMIM entry now available for this gene and condition.
The HGNC approved gene name is CIROZ

Sixteen individuals from 10 independently ascertained families with Left-right anomalies with or without Congenital Heart Defects, consistent with Heterotaxy. Family 1 is of European ancestry, and families 9 and 10 are from Central America, while all remaining families were of Middle Eastern background and known to be consanguineous.

Of these 16 affected individuals, three were affected fetuses subjected to termination of pregnancy, and two died in the first year of life due to complex cardiac phenotypes.
Sources: Literature
Fetal anomalies v5.6 CACHD1 Achchuthan Shanmugasundram gene: CACHD1 was added
gene: CACHD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACHD1 were set to 38158856
Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder, MONDO:0800439
Review for gene: CACHD1 was set to AMBER
Added comment: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant).

Of these, two cases from the fourth family are fetal cases. Excluding these two fatal cases, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one.

Facial dysmorphism and ear and genitourinary abnormalities were reported in the two fetal cases, while congenital malformations of the digestive tract was reported in one of them.

Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Fetal anomalies v3.157 USP14 Zornitza Stark gene: USP14 was added
gene: USP14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP14 were set to 38469793
Phenotypes for gene: USP14 were set to Syndromic disease MONDO:0002254, USP14-related
Review for gene: USP14 was set to AMBER
Added comment: PMID 38469793: biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. The fetus and the newborn had extensive brain malformations.
Sources: Literature
Fetal anomalies v3.156 PLD1 Arina Puzriakova commented on gene: PLD1: Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Fetal anomalies v3.109 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to intracranial hemorrhage; cerebral anomalies
Review for gene: ESAM was set to GREEN
Added comment: Four fetuses from three unrelated families (different LOF biallelic variants) with fetal intracranial hemorrhage. Fetal brain tissue from one of the affected individuals at 31 weeks' gestational age showed lack of ESAM staining in the capillary endothelial cells, thus confirming loss of ESAM. Another individual had an abnormal prenatal ultrasound and the pregnancy was terminated at 32 weeks' gestation, but no DNA was available to test for the familial variant.
Neurodevelopmental disorder with cerebral calcifications, hydrocephalus, focal white matter lesions, retina anomalies and dysmorphic features.
Sources: Literature
Fetal anomalies v3.99 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Fetal anomalies v3.94 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Fetal anomalies v2.14 PLXND1 Achchuthan Shanmugasundram gene: PLXND1 was added
gene: PLXND1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Truncus arteriosus, HP:0001660
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Sources: Literature
Fetal anomalies v1.977 AP1S2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Fetal anomalies v1.904 RAB11A Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber for now, but with a recommendation of GREEN rating following GMS expert review as to whether the brain anomaly/microcephaly phenotype observed in 5 individuals with missense variants in RAB11A is appropriate for this panel.
Fetal anomalies v1.900 RAB11A Eleanor Williams changed review comment from: PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described. For 3 of the 4 individuals there are brain MRI data which indicate brain abnormalities including partial agenesis of the corpus callosum, or thin corpus collosum.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Both are reported to have microcephaly (degree not stated) and brain anomalies (both with agenesis of corpus callosum, and one with additional abnormal cortical gyration, mylation abnormalites).; to: PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described. For 3 of the 4 individuals there are brain MRI data which indicate brain abnormalities including partial agenesis of the corpus callosum, or thin corpus collosum.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Both are reported to have microcephaly (degree not stated) and brain anomalies (both with agenesis of corpus callosum, and one with additional abnormal cortical gyration, myelination abnormalites).
Fetal anomalies v1.900 CHRM3 Rhiannon Mellis gene: CHRM3 was added
gene: CHRM3 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: CHRM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRM3 were set to PMID: 22077972; 31441039; 10944224
Phenotypes for gene: CHRM3 were set to Prune belly syndrome; Megacystis
Review for gene: CHRM3 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Discussed as a potential cause of megacystis. Currently Red on Panelapp CAKUT panel (2016) because at that time there was only 1 reported family and a mouse model. The unpublished data mentioned in that panelapp review (from Adrian Woolf, Manchester) is now published so now 2 families PMID: 22077972; 31441039 plus a mouse model PMID: 10944224. However, prenatal findings (distended bladder and unilateral hydronephrosis) only documented for one individual. More evidence of prenatal phenotype would be helpful.
Sources: Expert Review, Literature
Fetal anomalies v1.900 FTO Rhiannon Mellis gene: FTO was added
gene: FTO was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117
Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism
Review for gene: FTO was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Not Green on any panels (only 2 families reported to date). On OMIM: Growth retardation, developmental delay, facial dysmorphism. One fetal case reported by Monies et al 2019 (PMID: 31130284) with Dandy-Walker malformation, IUGR, and polyhydramnios. This fits with the phenotype reported in one consanguineous family with 9 affected individuals reported by Boissel 2009 PMID: 19559399. The other reported case is PMID: 26378117 - a homozygous missense variant in FTO was identified in a 21-month old girl who presented with growth retardation, failure to thrive, severely delayed development, Dysmorphic facial features, decreased brain parenchyma, delayed myelination, and a thin corpus callosum.
Sources: Expert Review, Literature
Fetal anomalies v1.827 RAC3 Rhiannon Mellis gene: RAC3 was added
gene: RAC3 was added to Fetal anomalies. Sources: Literature,Expert Review,NHS GMS
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC3 were set to 30293988; 29276006
Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RAC3 was set to GREEN
Added comment: This gene already has sufficient evidence for Green rating on the ID panel (see below) and now adding evidence (from NHS GMS testing) for prenatal phenotype to support Green rating for the Fetal Anomalies panel also: A RAC3 likely pathogenic missense variant has been identified postnatally in a baby that presented prenatally with absent corpus callosum, bilateral ventriculomegaly, cerebellar and brainstem hypoplasia detected on fetal ultrasound and MRI. The variant is judged by the child's clinical team to be causative of the clinical and radiological features in the child.

Copied from Green review on Intellectual Disability panel by Konstantinos Varvagiannis:

PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients.

All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance).

Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family.

Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006).
Sources: Literature, Expert Review, NHS GMS
Fetal anomalies v1.811 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. No prenatal findings were specifically mentioned but given the otherwise comparable clinical presentations, monoallelic inheritance may also be of relevance to this panel. Therefore, will flag this for further GMS review.
Fetal anomalies v1.749 LMNB2 Rhiannon Mellis gene: LMNB2 was added
gene: LMNB2 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB2 were set to PMID: 33033404
Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Expert Review, Literature
Fetal anomalies v1.749 LMNB1 Rhiannon Mellis gene: LMNB1 was added
gene: LMNB1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB1 were set to PMID: 33033404
Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant
Review for gene: LMNB1 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Literature, Expert Review
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Fetal anomalies v1.720 WLS Zornitza Stark gene: WLS was added
gene: WLS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to 34587386
Phenotypes for gene: WLS were set to structural congenital anomalies
Review for gene: WLS was set to GREEN
Added comment: - Homozygous variants in 10 affected persons from 5 unrelated families.
- Affected individuals had multiorgan defects, including microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Fetal anomalies v1.720 WNT9B Zornitza Stark gene: WNT9B was added
gene: WNT9B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WNT9B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT9B were set to 34145744
Phenotypes for gene: WNT9B were set to Renal agenesis/hypoplasia/dysplasia
Review for gene: WNT9B was set to AMBER
Added comment: WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. WNT9B−/− mice have renal agenesis/hypoplasia and reproductive tract abnormalities.

Lemire et al. (2021) report 4 individuals from 2 unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 had bilateral renal cystic dysplasia and chronic kidney disease, with 2 deceased siblings with bilateral renal hypoplasia/agenesis. The 3 affected family members were homozygous for a Gly317Arg missense variant in WNT9B. Proband from Family 2 had renal hypoplasia/dysplasia, chronic kidney disease, and was homozygous for a Pro5Alafs*52 nonsense variant in WNT9B. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance.

I wasn't sure which panel this is more pertinent to: we have added this gene to our CAKUT panel.
Sources: Literature
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.; to: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - sufficient cases (>3) of congenital hydrocephaly which may conceivably be detected prenatally.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.
Fetal anomalies v1.645 FOXP4 Ivone Leong gene: FOXP4 was added
gene: FOXP4 was added to Fetal anomalies. Sources: Literature
Q2_21_rating, Q2_21_phenotype tags were added to gene: FOXP4.
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not in OMIM.

This gene is present as an Amber gene on the Intellectual disability panel (Version 3.1052) with the following reviews:

"This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel? Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here. Sources: Literature
Zornitza Stark (Australian Genomics), 4 Nov 2020"

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 4 Dec 2020"

After discussion with the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to review by the GMS specialist group.
Sources: Literature
Fetal anomalies v1.627 WBP11 Eleanor Williams gene: WBP11 was added
gene: WBP11 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
Fetal anomalies v1.625 OTUD5 Arina Puzriakova gene: OTUD5 was added
gene: OTUD5 was added to Fetal anomalies. Sources: Expert Review
Q2_21_rating tags were added to gene: OTUD5.
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077; 33523931
Phenotypes for gene: OTUD5 were set to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, OMIM:301056
Review for gene: OTUD5 was set to GREEN
Added comment: OTUD5 is associated with a relevant phenotype in OMIM but not yet in Gene2Phenotype.

- PMID: 33131077 (2021) - 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals.

- PMID: 33523931 (2021) - Another 10 individuals from 7 families reported. Key features include poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.
Sources: Expert Review
Fetal anomalies v1.612 SUFU Arina Puzriakova changed review comment from: The patients described by Schroder et al 2020 (PMID: 33024317) display cerebellar abnormalities that were said to be within the milder range of the Joubert clinical spectrum. This gene will be flagged for review by the GMS team with regards to whether these features may conceivably be detected prenatally (added 'for-review' tag).

Note that these individuals harboured heterozygous truncating variants, and monoallelic variants in this gene have also previously been associated with Basal cell nevus syndrome and Medulloblastoma.; to: SUFU was reassessed in line with the recent expert review by Rhiannon Mellis (GOSH). The patients described by Schroder et al 2020 (PMID: 33024317) display cerebellar abnormalities that were said to be within the milder range of the Joubert clinical spectrum. However, it is unclear whether these features may conceivably be detected prenatally and therefore this gene will be flagged for review by the GMS team with regards to phenotypic fit for this panel (added 'for-review' tag).

Note that unlike the 2 Joubert syndrome families with biallelic variants reported by De Mori et al. (2017, PMID: 28965847), these individuals harboured heterozygous truncating variants in the SUFU gene. Monoallelic variants have previously been associated with basal cell nevus syndrome and medulloblastoma, and there was no evidence of tumours in any of the families described by Schroder et al.
Fetal anomalies v1.185 TBC1D32 Rhiannon Mellis gene: TBC1D32 was added
gene: TBC1D32 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to PMID: 32573025; 31130284; 32060556
Phenotypes for gene: TBC1D32 were set to OFD IX
Review for gene: TBC1D32 was set to GREEN
Added comment: Now 5 families reported:

The same group who reported the first individual with a ciliopathy phenotype (Adly et al 2014) now report two further unrelated fetal cases (Alsahan 2020, Monies et al 2019) with OFD/ciliopathy phenotype:

- One had polyhydramnios, hydrocephaly with enlarged biparietal diameter and dilated lateral ventricles, single nostril, anophthalmia, short long bones and echogenic lungs
- The other had holoprosencephaly, cyclops, cleft lip, ventricular septal defect, agenesis of corpus callosum, and club feet

- There are also two sib pairs (one Finnish, one Pakistani) reported by Hietamaki et al 2020 with TBC1D32 variants and a variable phenotype of pituitary hypoplasia +/- other midline defects, hydrocephalus, short limbs, polydactyly
Sources: Literature
Fetal anomalies v1.155 MN1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Multiple unrelated individuals (>20) described with a complex developmental disorder and de novo truncating MN1 variants. This gene will be flagged for review to determine whether the phenotype is fetally-relevant and there is enough evidence to include as Green.

Plausible that some features of the disorder, such as craniofacial abnormalities and structural brain anomalies may be detected prenatally. However based on published clinical descriptions, antenatal history was uneventful in most cases - but reports did include fetal brain anomalies (1), NICU admission (1) and IUGR (2). Similarly, neonatal problems were only reported in a few patients but included respiratory issues (3), abnormal ABR (1), congenital diaphragmatic hernia (1), perinatal hypoxia (1), congenital hypothyroidism (1), hearing impairment (1) and SCBU admission (1) (see Supplementary material in PMID: 31834374)
Fetal anomalies v1.108 GFRA1 Zornitza Stark gene: GFRA1 was added
gene: GFRA1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GFRA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFRA1 were set to 33020172
Phenotypes for gene: GFRA1 were set to Renal agenesis
Review for gene: GFRA1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic LOF variants identified in individuals with bilateral renal agenesis. GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system. Also relevant to the CAKUT panel.
Sources: Literature
Fetal anomalies v1.95 SLC20A1 Zornitza Stark gene: SLC20A1 was added
gene: SLC20A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC20A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A1 were set to 32850778; 27013921
Phenotypes for gene: SLC20A1 were set to Bladder-Exstrophy-Epispadias Complex (BEEC)
Review for gene: SLC20A1 was set to GREEN
gene: SLC20A1 was marked as current diagnostic
Added comment: Three individuals and animal model supporting role of this gene in urinary tract and urorectal development. We have included on our CAKUT panel.
Sources: Literature
Fetal anomalies v1.95 GDF2 Zornitza Stark gene: GDF2 was added
gene: GDF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GDF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDF2 were set to 32618121
Phenotypes for gene: GDF2 were set to Lymphatic dysplasia; hydrothorax; hydrops
Review for gene: GDF2 was set to RED
Added comment: Single family reported, two affected individuals. New MOI.

Monoallelic variants in this gene are associated with HHT/PAH.
Sources: Literature
Fetal anomalies v1.73 GDF1 Rhiannon Mellis gene: GDF1 was added
gene: GDF1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: GDF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GDF1 were set to PMID: 20413652; 28991257; 17924340
Phenotypes for gene: GDF1 were set to Congenital heart defects, multiple types; Right atrial isomerism (Ivemark)
Review for gene: GDF1 was set to GREEN
Added comment: Right atrial isomerism (AR): 5 sibs in one family PMID: 20413652; One unrelated individual with RAI, complex cardiac anomalies, abdominal heterotaxy and asplenia PMID: 28991257

Other varied CHD (including ToF, DORV, TGA) (AD): 8 unrelated individuals PMID 17924340

Reviewed for fetally relevant phenotype by Prof Lyn Chitty (Yes)

This gene appears on our local heterotaxy panel (NETRGL) and as Green on Panelapp Laterality disorders panel and Familial non-syndromic CHD panel.
Sources: Literature, Expert Review
Fetal anomalies v1.73 CFAP53 Rhiannon Mellis gene: CFAP53 was added
gene: CFAP53 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: CFAP53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP53 were set to PMID: 22577226; PMID: 25504577; PMID: 26531781
Phenotypes for gene: CFAP53 were set to Heterotaxy, visceral, 6, autosomal recessive; Dextrocardia; Transposition of the great arteries; gut malrotation; midline liver; inverted spleen
Review for gene: CFAP53 was set to GREEN
Added comment: Literature reports 6 individuals from 4 families and a zebrafish model PMID: 22577226, PMID: 25504577, PMID: 26531781

Reviewed for fetally relevant phenotype by Prof Lyn Chitty (yes).

This gene appears on our local heterotaxy panel (NETRGL) and on the Panelapp laterality disorders and non-syndromic CHD panels (Green)
Sources: Literature, Expert Review
Fetal anomalies v1.54 PSAT1 Rebecca Foulger commented on gene: PSAT1: PMID:25152457. Acuna-Hidalgo et al., 2014 report a rare AR disorder with severe malformations leading to prenatal or early postnatal lethality (Neu-Laxova syndrome). They identified variants in PHGDH, PSAT1 and PSPH in individuals with NLS, including 6 families with 3 different missense and frameshift PSAT1 variants which segregated with the disease.
Fetal anomalies v1.52 ALG9 Rebecca Foulger changed review comment from: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.; to: Comment on list classification: ALG9 congenital disorder of glycosylation has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.52 ALG9 Rebecca Foulger Added comment: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.30 EXOC3L2 Rebecca Foulger changed review comment from: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.; to: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family (reviewed briefly in PMID:28749478).
Fetal anomalies v1.30 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.
Fetal anomalies v1.26 POLE Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Amber to Green: Multiple cases of IUGR from 2 papers (PMID:25948378 and PMID:30503519). Phenotype relevant to panel, and sufficient evidence to support causation.; to: Comment on list classification: Originally added to panel as Amber based on PMID:30503519. Updated rating from Amber to Green with curation of additional paper PMID:25948378 who report a separate individual with IUGR. Phenotype relevant to panel, and sufficient evidence to support causation.
Fetal anomalies v1.20 POLE Rebecca Foulger gene: POLE was added
gene: POLE was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLE were set to 23230001
Phenotypes for gene: POLE were set to IUGR; severe growth failure of prenatal onset
Added comment: Added to panel based on prenatal phenotype reported in PMID:30503519: (Logan et al., 2018) report biallelic variants in POLE in 15 indivs from 12 families (mix of countries). All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. Phenotypically, affected individuals all had IUGR and severe growth failure of prenatal onset.
Sources: Literature
Fetal anomalies v1.0 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204
Phenotypes for gene: ATP1A2 were set to hydrops fetalis; microcephaly; arthrogryposis; extensive cortical malformations
Review for gene: ATP1A2 was set to AMBER
gene: ATP1A2 was marked as current diagnostic
Added comment: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities. Mouse model is perinatal lethal. This is a distinct phenotype from the mono allelic variants associated with alternating hemiplegia.
Sources: Expert list
Fetal anomalies v0.367 BICD2 Rebecca Foulger commented on gene: BICD2: PMID:28635954 (Storbeck et al., 2017) describe 3 individuals of independent families with severe severe arthrogryposis multiplex congenita (AMC), respiratory insufficiency, and early lethality caused by three BICD2 variants (p.Arg694Cys, p.Gln194Arg and p.Cys542Trp, 2 of which are proven to be de novo). They also describe an asymptomatic women with subclinical findings with the previously described p.(Thr703Met) variant.
Fetal anomalies v0.342 ANAPC1 Rebecca Foulger commented on gene: ANAPC1: Added ANAPC1 to the Fetal anomalies panel and rated Green on approval from Anna de Burca and Richard Scott (Genomics England Clinical team). Note yet associated with a disorder in OMIM but evidence comes from PMID:31303264 (Ajeawung et al., 2019) where they report 10 individuals (7 families including 3 families of Amish ancestry) with Rothmund-Thomson Syndrome Type 1 and biallelic variants in ANAPC1. Phenotype includes skeletal abnormalities and short stature. All individuals carried an intronic splicing variant (NM_022662.3:c.2705−198C>T): in 3 Amish families plus individual 4, this intronic variant was found in a homozygous state. In the remaining families, the intronic variant was found in trans with one of three other LOF variants. Therefore sufficient cases to support a Green rating plus fetally-relevant phenotype.
Fetal anomalies v0.311 TCF20 Rebecca Foulger edited their review of gene: TCF20: Added comment: As agreed with Anna de Burca (Genomics England Clinical team): Keep TCF20 as Amber: the structural phenotypes are variable (and largely mild). All individuals have ID/DD but the accompanying dysmorphic features are inconsistent, and the authors suggest additional genes may be responsible/modifying- some of the patients had variants in additional genes (or the phenotypes might be very very rare).; Changed publications: 30739909, 30819258
Fetal anomalies v0.311 IDUA Rebecca Foulger edited their review of gene: IDUA: Added comment: This gene was reviewed by Anna de Burca (Genomics England Clinical Team) under the category of storage disorders. Outcome of review: Rate as Green-Umbilical hernia, may cause hydrops.; Changed rating: GREEN
Fetal anomalies v0.248 CNOT1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting clinical review. In summary: Sufficient (five) unrelated cases from two 2019 papers (PMID:31006513 and PMID:31006510) with holoprosencephaly, and pancreatic agenesis in 4/5 cases. The same heterozygous variant was recorded in all five individuals and authors of PMID:31006513 suggest phenotype is variant-specific rather than LOF. Mice require a homozygous variant to display a phenotype.
Fetal anomalies v0.247 CNOT1 Rebecca Foulger commented on gene: CNOT1: Kruszka et al., 2019 (PMID:31006510) report two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CNOT1. (c.1603C>T [p.Arg535Cys]). Proband 1 was born after a pregnancy complicated by IUGR. Additional medical problems include diabetes, pancreatice exocrine insufficiency and facial characteristics. No diabetic or pancreatic phenotype was recorded for proband 2.
Fetal anomalies v0.247 CNOT1 Rebecca Foulger commented on gene: CNOT1: De Franco et al., 2019 (PMID:31006513) investigated a cohort of 107 individuals with pancreatic agenesis and definite/possible holoprosencephaly, and identified a heterozygous missense variant in CNOT1 (NM_016284.4; c.1603C>T (p.Arg535Cys)) in three unrelated individuals. The variant was de novo in two individuals, and was not present in the DNA sample from the third individual's father (maternal sample was unavailable). Mice required a homozygous variant to display a phenotype: in homozygous mice embryos (embryonically lethal) morphological abnormalities were apparent upon dissection including edema, a smaller dorsal pancreas, and exencephaly. The DDD study identified de novo CNOT1 variants in three individuals with developmental delay but none had holoprosencephaly, diabetes or pancreatic or neurological structural malformations. The authors therefore suggest that a mutation-specific mechanism rather than LOF is responsible for the pancreatic and holoprosencephaly phenotype.
Fetal anomalies v0.199 COG4 Rebecca Foulger commented on gene: COG4: The evidence for Saul-Wilson syndrome (MIM:618150) comes from one 2018 paper (PMID:30290151): Ferreira et al. (PMID:30290151, 2018) identified 2 different de novo heterozygous vaiants in the COG4 gene in 14 individuals, c.1546G-A and c.1546G-C both of which give rise to an identical missense mutation (G516R). Functional analysis shows that a stable protein is produced and, despite Golgi collapse, glycosylation is relatively normal. Given the DD-G2P Disease confidence rating is 'probable' (March 2019), only a missense variant has been reported, and functional evidence doesn't yet show the effect of the protein alteration, I have kept the MOI for COG4 on the Fetal anomalies panel as biallelic (for the confirmed glycosylation disorder) and not included the monoallelic Saul-Wilson syndrome on the panel at this stage.
Fetal anomalies v0.72 ARCN1 Rebecca Foulger commented on gene: ARCN1: Additional information to support Green rating: 4 patients from 3 families in Izumi et al., 27476655, 2016 of patients with Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay. All individuals had short stature but just 2 families (subjects 3 and 4 are related) with microcephaly. Genomics England Clinical team (Helen Brittain) notes that IUGR is listed as a feature therefore could present in a fetus, also a smattering of structural malformations e.g. CHD / cleft which might also be detected in utero so probably OK to include.
Fetal anomalies v0.63 USP18 Rebecca Foulger edited their review of gene: USP18: Added comment: Rated as 'Probable' in original PAGE list. Rated green on 'Intracerebral calcification disorders' panel and phenotype (pseudo-TORCH syndrome) is appropriate for Fetal panel, as noted by Helen Brittain and Anna de Burca (Genomics England Clinical team). However, kept rating as Amber for now based on insufficient evidence to support causation: One publication (Meuwissen et al. 2016, PMID:27325888) with two families (Turkish and German) with pseudo-TORCH syndrome-2 and homozygous or compound het variants in USP18. Segregation shown in 5 affected individuals plus an unaffected sibling. Cells from patients in both families showed complete absence of the USP18 protein.; Changed publications: 27325888; Changed phenotypes: Pseudo-TORCH syndrome 2, 617397
Fetal anomalies v0.63 EPHB4 Rebecca Foulger edited their review of gene: EPHB4: Added comment: Additional details for change of rating from Amber ('probable' PAGE rating) to Green: Phenotype is fetally-relevant, and rated green on the 'Primary lymphoedema' panel. Sufficient evidence to support hydrops fetalis association as part of MIM:617300, with 3 variants listed in OMIM from 3 families, each with multiple affected individuals (PMIDs:27400125 and 29905864).; Changed rating: GREEN; Changed publications: 27400125, 29905864; Changed phenotypes: Lymphatic malformation 7, 617300
Fetal anomalies v0.34 ATAD3A Anna de Burca commented on gene: ATAD3A: PMID: 27640307 reports a recurrent de novo variant in ATAD3A in five unrelated individuals with developmental delay and hypotonia. Some individuals had peripheral neuropathy, optic atrophy and hypertrophic cardiomyopathy. A toxic gain of function mechanism was postulated. PMID: 28327206 reports an additional case with the same de novo variant. This individual had delayed motor development and hypotonia. PMID: 27640307 also reports a biallelic missense variant in siblings of distantly related parents with motor and speech delay, hypotonia, cerebellar atrophy, ataxia, seizures, muscle weakness, cataracts and optic nerve hypoplasia. There is insufficient evidence for this association at present. Therefore, this gene should be classified green with regard to monoallelic gain of function only.
Fetal anomalies v0.9 IDUA Rebecca Foulger reviewed gene: IDUA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 IDUA Rebecca Foulger Added phenotypes MUCOPOLYSACCHARIDOSIS TYPE 1H for gene: IDUA
Fetal anomalies v0.1 IDUA Rebecca Foulger Added phenotypes MUCOPOLYSACCHARIDOSIS TYPE 1H/S for gene: IDUA
Fetal anomalies v0.1 IDUA Rebecca Foulger gene: IDUA was added
gene: IDUA was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IDUA were set to MUCOPOLYSACCHARIDOSIS TYPE 1S