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Intestinal failure or congenital diarrhoea v3.1 Sarah Leigh Panel version 3.0 has been signed off on 2023-03-22
Intestinal failure or congenital diarrhoea v3.0 Sarah Leigh promoted panel to version 3.0
Intestinal failure or congenital diarrhoea v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2022-11-30
Intestinal failure or congenital diarrhoea v2.0 Arina Puzriakova promoted panel to version 2.0
Intestinal failure or congenital diarrhoea v1.50 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from Obesity with impaired prohormone processing, OMIM:600955 to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Intestinal failure or congenital diarrhoea v1.48 SI Eleanor Williams commented on gene: SI
Intestinal failure or congenital diarrhoea v1.48 PCSK1 Eleanor Williams commented on gene: PCSK1: Two patients reported in PMID: 9207799 and PMID: 14617756 are reported to have PC1 deficiency with a obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones phenotype. The second patient (PMID: 14617756) had severe refractory neonatal diarrhea, malabsorptive in type and re-investigation of the first patient showed marked small-intestinal absorptive dysfunction. Both patients were found to have compound heterozygous protein altering variants in PC1 (now known as PCSK1). PMID: 17595246 - report a 3rd individual who was homozygous for a novel missense mutation Ser307Leu in PCSK1 who presented with obesity and persistent diarrhea.
Intestinal failure or congenital diarrhoea v1.47 TERT Ivone Leong gene: TERT was added
gene: TERT was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: TERT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TERT were set to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Intestinal failure or congenital diarrhoea v1.47 SI Ivone Leong gene: SI was added
gene: SI was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: SI was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SI were set to Sucrase-isomaltase deficiency, congenital, OMIM:222900
Intestinal failure or congenital diarrhoea v1.47 PCSK1 Ivone Leong gene: PCSK1 was added
gene: PCSK1 was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: PCSK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PCSK1 were set to Obesity with impaired prohormone processing, OMIM:600955
Intestinal failure or congenital diarrhoea v1.47 FAT4 Ivone Leong gene: FAT4 was added
gene: FAT4 was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: FAT4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAT4 were set to Hennekam lymphangiectasia-lymphedema syndrome 2, OMIM:616006
Intestinal failure or congenital diarrhoea v1.47 CD55 Ivone Leong gene: CD55 was added
gene: CD55 was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: CD55 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CD55 were set to Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy, OMIM:226300
Intestinal failure or congenital diarrhoea v1.47 CCBE1 Ivone Leong gene: CCBE1 was added
gene: CCBE1 was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: CCBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CCBE1 were set to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
Intestinal failure or congenital diarrhoea v1.47 ADAMTS3 Ivone Leong gene: ADAMTS3 was added
gene: ADAMTS3 was added to Intestinal failure. Sources: Expert Review Green
Mode of inheritance for gene: ADAMTS3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ADAMTS3 were set to Hennekam lymphangiectasia-lymphedema syndrome 3, OMIM:618154
Intestinal failure or congenital diarrhoea v1.44 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, OMIM:251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Intestinal failure or congenital diarrhoea v1.43 AGR2 Ivone Leong Entity copied from Respiratory ciliopathies including non-CF bronchiectasis v1.53
Intestinal failure or congenital diarrhoea v1.43 AGR2 Ivone Leong gene: AGR2 was added
gene: AGR2 was added to Intestinal failure. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: AGR2.
Mode of inheritance for gene: AGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGR2 were set to 34952832
Phenotypes for gene: AGR2 were set to Cystic fibrosis-like syndrome; chronic diarrhoea
Penetrance for gene: AGR2 were set to Complete
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.

After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.36 IL37 Arina Puzriakova gene: IL37 was added
gene: IL37 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Classified gene: TMPRSS15 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.35 TMPRSS15 Ivone Leong Gene: tmprss15 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Classified gene: PLVAP as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.33 PLVAP Ivone Leong Gene: plvap has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.32 PLVAP Ivone Leong Added comment: Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia.

PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia.

PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis.

PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Intestinal failure or congenital diarrhoea v1.31 PLVAP Ivone Leong Phenotypes for gene: PLVAP were changed from Diarrhoea 10, protein-losing enteropathy type, MIM# 618183 to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Classified gene: NEUROG3 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.30 NEUROG3 Ivone Leong Gene: neurog3 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Classified gene: WNT2B as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.28 WNT2B Ivone Leong Gene: wnt2b has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.27 WNT2B Ivone Leong Added comment: Comment on publications: PMID: 33526876 reports an additional unrelated case. Patient is of Haitian descent (previous cases described in PMID:29909964 are of Vietnamese and Kuwaiti origins). Patient has neonatal onset diarrhoea with metabolic acidosis and failure to thrive. Patient also has bilateral microcornea and corneal clouding. Patient also presented with ambiguous genitalia and diagnosed with 46,XX testicular DSD.

The authors reviewed the clinical findings of the previous patients they had reported on (PMID:29909964) and found that the Kuwaiti patients had bilateral microcornea, corneal neovascularization and thick corneas (I-2), and bilateral iridocorneal adhesions, congenital cataract, and iris coloboma (I-3). The gonadal findings in the Haitian patient was not seen in any of the other affected patients.
Intestinal failure or congenital diarrhoea v1.24 STXBP2 Ivone Leong Phenotypes for gene: STXBP2 were changed from Hemophagocytic lymphohistiocytosis, familial, 5 613101 to Hemophagocytic lymphohistiocytosis, familial, 5, OMIM:613101
Intestinal failure or congenital diarrhoea v1.23 STX3 Ivone Leong Phenotypes for gene: STX3 were changed from Microvillus inclusion disease; congenital diarrheal disorder to Microvillus inclusion disease, MONDO:0009635; diarrheal disorder, MONDO:0001673
Intestinal failure or congenital diarrhoea v1.19 SKIV2L Ivone Leong Added comment: Comment on publications: 27537055 - a pathogenic variant (heterozygous state) in this gene was reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Intestinal failure or congenital diarrhoea v1.19 SKIV2L Ivone Leong Publications for gene: SKIV2L were set to 22444670; 27302973; 27537055 - a pathogenic variant (heterozygous state) in this gene was reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Intestinal failure or congenital diarrhoea v1.17 MYO5B Ivone Leong Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850 to Microvillus inclusion disease, OMIM:251850
Intestinal failure or congenital diarrhoea v1.13 DGAT1 Ivone Leong Phenotypes for gene: DGAT1 were changed from Congenital diarrheal disorder to Congenital diarrheal disorder; ?Diarrhea 7, protein-losing enteropathy type, OMIM:615863
Intestinal failure or congenital diarrhoea v1.12 FLNA Ivone Leong Classified gene: FLNA as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.12 FLNA Ivone Leong Added comment: Comment on list classification: New gene added by Miranda Durkie (Genetics). This gene is associated with a relevant disorder on OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.12 FLNA Ivone Leong Gene: flna has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.9 CLMP Ivone Leong Classified gene: CLMP as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.9 CLMP Ivone Leong Added comment: Comment on list classification: New gene added by Miranda Durkie (Genetics). This gene is associated with a relevant disorder on OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.9 CLMP Ivone Leong Gene: clmp has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.5 PLVAP Zornitza Stark gene: PLVAP was added
gene: PLVAP was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, MIM# 618183
Review for gene: PLVAP was set to GREEN
gene: PLVAP was marked as current diagnostic
Added comment: Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients.

Four unrelated families reported.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 TMPRSS15 Zornitza Stark gene: TMPRSS15 was added
gene: TMPRSS15 was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: TMPRSS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMPRSS15 were set to 11719902; 33061943
Phenotypes for gene: TMPRSS15 were set to Enterokinase deficiency, MIM# 226200
Review for gene: TMPRSS15 was set to GREEN
gene: TMPRSS15 was marked as current diagnostic
Added comment: Deficiency of enterokinase, a sequence-specific protease that activates trypsinogen and has a major role in protein digestion, is an autosomal recessive disorder characterised by severe protein malabsorption in early infancy, with failure to thrive, chronic diarrhoea, and generalized oedema. In adulthood, patients have normal body weight and no gastrointestinal symptoms, even when pancreatic enzyme supplements are discontinued. Three unrelated families reported with molecularly confirmed diagnosis.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 WNT2B Zornitza Stark gene: WNT2B was added
gene: WNT2B was added to Intestinal failure. Sources: Expert Review
Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT2B were set to 29909964
Phenotypes for gene: WNT2B were set to Diarrhoea 9, MIM# 618168
Review for gene: WNT2B was set to GREEN
gene: WNT2B was marked as current diagnostic
Added comment: Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function.

Borderline Green/Amber.
Sources: Expert Review
Intestinal failure or congenital diarrhoea v1.5 AP1S1 Zornitza Stark gene: AP1S1 was added
gene: AP1S1 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure
Review for gene: AP1S1 was set to AMBER
Added comment: - Established gene-disease association with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants.
Sources: Literature
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Intestinal failure or congenital diarrhoea v1.5 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v1.4 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; Haemorrhagic diarrhoea; Dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Intestinal failure or congenital diarrhoea v1.3 Ellen McDonagh Panel version has been signed off
Intestinal failure or congenital diarrhoea v1.0 Ivone Leong promoted panel to version 1.0
Intestinal failure or congenital diarrhoea v0.32 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Intestinal failure or congenital diarrhoea v0.18 STX3 Ivone Leong Gene: stx3 has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.16 TTC37 Ivone Leong Gene: ttc37 has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.16 STXBP2 Ivone Leong Gene: stxbp2 has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.16 STX3 Ivone Leong Phenotypes for gene: STX3 were changed from to Microvillus inclusion disease; congenital diarrheal disorder
Intestinal failure or congenital diarrhoea v0.12 SKIV2L Ivone Leong Gene: skiv2l has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.12 MYO5B Ivone Leong Gene: myo5b has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.12 GUCY2C Ivone Leong Gene: gucy2c has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.12 EPCAM Ivone Leong Gene: epcam has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.12 DGAT1 Ivone Leong Gene: dgat1 has been classified as Green List (High Evidence).
Intestinal failure or congenital diarrhoea v0.10 STX3 Miranda Durkie reviewed gene: STX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24726755, 29266534; Phenotypes: Microvillus inclusion disease, congenital diarrheal disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intestinal failure or congenital diarrhoea v0.10 STXBP2 Ivone Leong Source Other was added to STXBP2.
Mode of inheritance for gene STXBP2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Hemophagocytic lymphohistiocytosis, familial, 5 613101 for gene: STXBP2
Publications for gene STXBP2 were changed from to 20798128; 19804848
Intestinal failure or congenital diarrhoea v0.10 SKIV2L Ivone Leong Source Other was added to SKIV2L.
Mode of inheritance for gene SKIV2L was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Trichohepatoenteric syndrome 2 614602 for gene: SKIV2L
Publications for gene SKIV2L were changed from to 22444670; 27302973; 27537055 - a pathogenic variant (heterozygous state) in this gene was reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Intestinal failure or congenital diarrhoea v0.8 MYO5B Ivone Leong Phenotypes for gene: MYO5B were changed from to Microvillus inclusion disease, 251850
Intestinal failure or congenital diarrhoea v0.5 STX3 Anna de Burca reviewed gene: STX3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 24726755; Phenotypes: Microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intestinal failure or congenital diarrhoea v0.5 MYO5B Anna de Burca reviewed gene: MYO5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24014347, 29266534; Phenotypes: Microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal