Activity

Filter

Cancel
Date Panel Item Activity
25 actions
Fetal anomalies v7.11 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.
Fetal anomalies v7.6 RNF2 Ida Ertmanska gene: RNF2 was added
gene: RNF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376; 40831499
Phenotypes for gene: RNF2 were set to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Review for gene: RNF2 was set to GREEN
Added comment: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
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).
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 v6.12 MYH3 Arina Puzriakova Phenotypes for gene: MYH3 were changed from DISTAL ARTHROGRYPOSIS TYPE 2B; DISTAL ARTHROGRYPOSIS TYPE 2A to Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM:193700 (AD); Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM:618436 (AD); Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110 (AD); Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 (AR)
Fetal anomalies v3.155 GRM1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Zornitza Stark. Could not find any evidence of prenatal phenotypes in patients with GRM1 variants.
Fetal anomalies v3.78 WNT9B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Not yet associated with any phenotype in OMIM or G2P. Rating Amber as to date, only two cases have been reported in one paper but with a watchlist tag to monitor for additional cases.
Fetal anomalies v1.879 LONP1 Arina Puzriakova commented on gene: LONP1: Added 'watchlist_moi' tag to monitor recently reported association with congenital diaphragmatic hernia as highlighted in review by Zornitza Stark (Australian Genomics)
Fetal anomalies v1.705 PRKD1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was reassessed following a recent review by Zornitza Stark highlighting the potential involvement of biallelic variants. Currently the evidence for biallelic inheritance only suffices for an Amber rating and so I have kept the MOI as monoallelic but with a 'watchlist_MOI' tag to monitor for additional evidence. The Genomics England pipeline would still pick up biallelic cases under the current MOI.
Fetal anomalies v1.692 MYOD1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics) on Congenital myopathy panel. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association on this panel (Fetal anomalies). Therefore, this gene has been given an Amber rating.
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 v1.617 SLC20A1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to promote to Green.

At least three unrelated families with a BEEC phenotype (fetally-relevant) and different heterozygous variants in this gene (PMID: 32850778). In vitro assays and zebrafish model support pathogenicity.
Fetal anomalies v1.219 GDF2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family with 2 sibs affected by lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis. Homozygous truncating variant in GDF2 was detected which segregated with the disorder (PMID:32618121).

Rating Red as additional cases/functional evidence required to corroborate this gene-disease association.
Fetal anomalies v1.215 GFRA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Two unrelated families with non-syndromic bilateral renal agenesis, detected during the prenatal period, and distinct homozygous LoF variants in GFRA1. Animal models support a role in renal morphogenesis (PMID:33020172).

Rating Amber awaiting further cases/clinical evidence prior to inclusion as diagnositc-grade.
Fetal anomalies v1.184 NUAK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single consanguineous family with three consecutive fetuses with anencephaly. Exome sequencing revealed a recessive 21-bp in-frame deletion in NUAK2 segregating with the disease. Pathogenicity is supported by in vitro and animal model data.

Rating Amber, awaiting further cases/clinical evidence prior to inclusion as diagnostic-grade (added 'watchlist' tag)
Fetal anomalies v1.183 AMBRA1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases and supportive functional data. However, only a single publication linking this gene to human disease at present (PMID:32333458). Segregation data was not provided and penetrance remains unclear. AMBRA1 was investigated by targeted sequencing and so there also is a possibility of variants in other genes.

Currently the evidence is insufficient for a Green rating, but this may be revised if further cases/clinical evidence arise (added 'watchlist' tag)
Fetal anomalies v1.180 CALCRL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family with recurrent hydrops fetalis (PMID:30115739), supported by in vitro and animal model data. Rating Red as additional cases required to corroborate this gene-disease association.
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Added to panel with Amber review by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype. 2 families reported in PMID:30690204 with a fetally-relevant phenotype (including fetal hydrops). Therefore rated Amber awaiting further cases.
Fetal anomalies v1.45 AHCY Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. Two unrelated families with hydrops reported (PMID:30121674, 20852937). Note that previous reports of AHCY deficiency do not include hydrops (e.g. PMID:15024124). Overall, phenotype is relevant to the panel but currently insufficient evidence for Green rating. Rated Amber awaiting further evidence.
Fetal anomalies v0.345 FAM58A Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from MONOALLELIC to X-linked dominant. Although monoallelic inheritance is currently listed in DDG2P for STAR SYNDROME, FAM58A (CCNQ) is an X-linked gene.
Fetal anomalies v0.161 STAR Rebecca Foulger edited their review of gene: STAR: 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: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.; Changed rating: GREEN
Fetal anomalies v0.9 STAR Rebecca Foulger reviewed gene: STAR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.9 FAM58A Rebecca Foulger commented on gene: FAM58A: DDG2P rating in original PAGE list: Confirmed for STAR SYNDROME
Fetal anomalies v0.1 STAR Rebecca Foulger gene: STAR was added
gene: STAR was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STAR were set to CHOLESTEROL DESMOLASE-DEFICIENT CONGENITAL ADRENAL HYPERPLASIA
Fetal anomalies v0.1 FAM58A Rebecca Foulger gene: FAM58A was added
gene: FAM58A was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: FAM58A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: FAM58A were set to STAR SYNDROME