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| Fetal anomalies v6.183 | FGFR1 |
Ida Ertmanska changed review comment from: PMID: 27055092 Mazen et al., 2016 Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease. PMID: 25394172 Villanueva et al., 2015 7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous. P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members. In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance. PMID: 23812909 Simonis et al., 2013 6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing. PMID: 23154428 Jarzabek et al., 2012 5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations. P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits). FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).; to: PMID: 27055092 Mazen et al., 2016 Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease. PMID: 25394172 Villanueva et al., 2015 7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous. P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members. In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance. PMID: 23812909 Simonis et al., 2013 6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). Fetal case (patient 7) had no FGFR1 mutation detected. PMID: 23154428 Jarzabek et al., 2012 5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations. P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits). FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026). |
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| Fetal anomalies v6.14 | PDE12 |
Achchuthan Shanmugasundram changed review comment from: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature; to: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Of these, the patient from family 2 (died on day 2 after birth), and the two foetuses from family 3 had foetal anomalies detected via prenatal ultrasound. The patient from family 2 had brain anomalies. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses from family 3 and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
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| Fetal anomalies v6.14 | PDE12 |
Achchuthan Shanmugasundram gene: PDE12 was added gene: PDE12 was added to Fetal anomalies. Sources: Literature Q3_25_promote_green tags were added to gene: PDE12. Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDE12 were set to 39567835 Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970 Review for gene: PDE12 was set to GREEN Added comment: PMID:39567835 (2025) reported five cases (three live-borns and two foetuses) from three unrelated families presenting with severe early-onset mitochondrial disease. They showed wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. In family 1, one of the two patients died at 3 months of age, while patient from family 2 died at day 2. Increased nuchal translucency, severe intra-uterine growth retardation, hydrops and cystic hygroma was noted in one of the two foetuses by prenatal ultrasound and the pregnancy ended spontaneously at 22 gestational weeks. Nuchal translucency and absence of foetal movements were observed in the other foetus, which was terminated at 19 weeks. All three families harboured a different homozygous variant in PDE12 gene (p.Tyr155Cys, p.Gly372Glu & p.Arg41Pro) as identified by whole-exome sequencing. Based on the gnomAD database, all three missense variants were reported to be rare in general population. Functional evidence from patient fibroblast studies showed reduced PDE12 protein and accumulation of abnormally polyadenylated mitochondrial tRNAs/rRNAs, causing disrupted mitochondrial RNA processing. In addition, in silico modeling of the variants also suggested loss of function. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
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| Fetal anomalies v5.16 | TYROBP | Achchuthan Shanmugasundram commented on gene: TYROBP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v5.15 | TYROBP | Sarah Graham reviewed gene: TYROBP: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, MIM#221770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v5.13 | TYROBP |
Achchuthan Shanmugasundram gene: TYROBP was added gene: TYROBP was added to Fetal anomalies. Sources: NHS GMS,Expert Review Red Mode of inheritance for gene: TYROBP was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TYROBP were set to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, OMIM:221770 |
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| Fetal anomalies v4.3 | ARV1 |
Sarah Graham gene: ARV1 was added gene: ARV1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ARV1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARV1 were set to PMID: 36307859; 34296759 Review for gene: ARV1 was set to AMBER Added comment: Biallelic loss-of-function variants associated with autosomal recessive developmental and epileptic encephalopathy-38 (DEE38). Biallelic variants reported prenatally in 3 families (4 fetuses) in association with abnormal scan findings, particularly renal abnormalities. Renal abnormalities are not a common postnatal finding in this disorder, so causal relationship to scan findings is unclear. Salian 2021 PMID: 34296759, patient 3 - compound heterozygous frameshift and missense variants, p.(Pro174Alafs*14) and p.(Cys34Tyr), with prenatal hydronephrosis, postnatally profound ID, seizures, genitourinary abnormalities. Salian 2021 PMID: 34296759, Patients 5/6 (successive pregnancies of consanguineous parents) - homozygous c.674-1G>A; patient 5 termination at week 22 due to megaureter, small femora and humeri and narrow thorax; patient 6 NT 6.3 mm at week 14, bilaterally dilated renal pelvis at week 16+1. Fu 2022 PMID: 36307859 - compound het frameshift variants, p.(Glu137Asnfs*13) and p.(Pro174Alafs*14), reported in a fetus with dilation of lateral ventricles and polyhydramnios. Sources: Literature |
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| Fetal anomalies v1.49 | ALG9 |
Rebecca Foulger changed review comment from: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero , they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.; to: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys. |
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| Fetal anomalies v1.49 | ALG9 |
Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero , they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys. |
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| Fetal anomalies v0.165 | TYRP1 |
Rebecca Foulger Source Expert Review Red was added to TYRP1. Rating Changed from Green List (high evidence) to Red List (low evidence) |
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| Fetal anomalies v0.165 | TYR |
Rebecca Foulger Source Expert Review Red was added to TYR. Rating Changed from Green List (high evidence) to Red List (low evidence) |
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| Fetal anomalies v0.161 | TYRP1 | Rebecca Foulger edited their review of gene: TYRP1: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Phenotype is not fetally-relevant. Action taken: Demoted TYRP1 gene rating from Green to Red.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.161 | TYR | Rebecca Foulger edited their review of gene: TYR: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Phenotype is not fetally-relevant. Action taken: Demoted TYR gene rating from Green to Red.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | TYRP1 | Rebecca Foulger reviewed gene: TYRP1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | TYR | Rebecca Foulger reviewed gene: TYR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | HSD17B10 | Rebecca Foulger commented on gene: HSD17B10: DDG2P rating in original PAGE list: Confirmed for 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY and Confirmed for MENTAL RETARDATION SYNDROMIC X-LINKED TYPE 10. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.9 | HPD | Rebecca Foulger commented on gene: HPD: DDG2P rating in original PAGE list: Probable for HAWKINSINURIA and Probable for TYROSINEMIA TYPE 3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | TYRP1 |
Rebecca Foulger gene: TYRP1 was added gene: TYRP1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: TYRP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TYRP1 were set to OCULOCUTANEOUS ALBINISM TYPE 3 |
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| Fetal anomalies v0.1 | TYR |
Rebecca Foulger gene: TYR was added gene: TYR was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: TYR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TYR were set to OCULOCUTANEOUS ALBINISM TYPE 1 |
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| Fetal anomalies v0.1 | TAT |
Rebecca Foulger gene: TAT was added gene: TAT was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: TAT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TAT were set to TYROSINEMIA TYPE 2 |
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| Fetal anomalies v0.1 | HSD17B10 |
Rebecca Foulger gene: HSD17B10 was added gene: HSD17B10 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: HSD17B10 were set to 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY |
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| Fetal anomalies v0.1 | HPD | Rebecca Foulger Added phenotypes TYROSINEMIA TYPE 3 for gene: HPD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1 | FAH |
Rebecca Foulger gene: FAH was added gene: FAH was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FAH were set to TYROSINEMIA TYPE 1 |
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