| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Paediatric disorders - additional genes v3.8 | NOTCH3 |
Arina Puzriakova gene: NOTCH3 was added gene: NOTCH3 was added to Paediatric disorders - additional genes. Sources: NHS GMS Q4_23_promote_green, Q4_23_expert_review tags were added to gene: NOTCH3. Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NOTCH3 were set to 25394726 Phenotypes for gene: NOTCH3 were set to Lateral meningocele syndrome, OMIM:130720 Mode of pathogenicity for gene: NOTCH3 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: NOTCH3 was set to GREEN Added comment: Monoallelic variants in the NOTCH3 gene are associated with multiple phenotypes including CADASIL (MIM# 125310), Lateral Meningocele syndrome (MIM# 130720), and Myofibromatosis (MIM# 615293). Currently, CADASIL and myofibromatosis phenotypes are covered by several PanelApp panels; however, Lateral Meningocele syndrome is not - there is enough evidence to support inclusion of this gene-disease association on a diagnostic-grade panel. At least 5 unrelated de novo cases have been reported in literature (PMID: 25394726). All variants are truncating and cluster in the last exon of NOTCH3. Truncated proteins are predicted to cause increased notch signalling. An additional case was identified in Genomics England's Clinical Variant Archive (CVA) dataset via the Diagnostic Discovery initiative. The participant was recruited with Lateral Meningocele syndrome (inclusive of hypertelorism, high palate, dural ectasia, high pitched voice) and a diagnostically reported variant in the last exon of this gene was returned, lending further support to adding this gene to the panel. R27 appears to be the most phenotypically relevant panel for detecting Lateral Meningocele syndrome; however, the possibility of incidental findings of CADASIL needs to be considered. Both phenotypes are caused by GoF variants but those associated with CADASIL are located in exons 2-24 whereas variants in Lateral Meningocele found in exon 33 (last exon). Given the risk of incidental findings without a mechanism to delineate the types of variants that are prioritised via each panel, the best route for inclusion of Lateral Meningocele syndrome in PanelApp will be flagged for further NHSE expert discussion at the next GMS panel update release. Sources: NHS GMS |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v3.2 | WNT9B |
Arina Puzriakova gene: WNT9B was added gene: WNT9B was added to Paediatric disorders - additional genes. Sources: Literature,Expert Review Amber watchlist tags were added to gene: WNT9B. 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v2.8 | PLXND1 |
Achchuthan Shanmugasundram gene: PLXND1 was added gene: PLXND1 was added to Paediatric disorders - additional genes. 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v2.4 | PAPPA2 |
Arina Puzriakova gene: PAPPA2 was added gene: PAPPA2 was added to Paediatric disorders - additional genes. Sources: Expert list Q1_23_promote_green tags were added to gene: PAPPA2. Mode of inheritance for gene: PAPPA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAPPA2 were set to 26902202; 33875846; 34272725 Phenotypes for gene: PAPPA2 were set to Short stature, Dauber-Argente type, OMIM:619489 Added comment: At least 9 individuals from 5 unrelated families reported in literature with biallelic variants in this gene (PMID: 26902202; 33875846; 34272725). Clinical presentation is most notable for short stature, mild/moderate microcephaly, and dysmorphic features. Growth restriction typically becomes apparent with age. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v2.2 | TOR1AIP1 |
Arina Puzriakova gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Paediatric disorders - additional genes. Sources: Expert list Q4_22_promote_green tags were added to gene: TOR1AIP1. Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 24856141; 25425325; 27342937; 30723199; 31299614; 32055997; 33215087; 34164833 Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072 Review for gene: TOR1AIP1 was set to GREEN Added comment: Gene was initially added to the Cardiomyopathy panel; however, after NHS GMS review it was determined that R27 (congenital malformation/syndromic) panel is more appropriate. Therefore adding here with the recommendation of upgrading to Green status at the next review. ----- Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype. At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here. Patients present a severe multisystem phenotype with muscular dystrophy being the prominent feature observed in at least one case in each family, but additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam). Note that one additional homozygous case has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325). Biallelic variants have also been linked to a congenital myasthenic syndrome in two unrelated families (PMID: 33215087; 34164833). Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.107 | FOXI3 |
Arina Puzriakova gene: FOXI3 was added gene: FOXI3 was added to Paediatric disorders - additional genes. Sources: Expert Review Q4_22_promote_green tags were added to gene: FOXI3. Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXI3 were set to 36260083; 25655429; 18787161; 24650709 Phenotypes for gene: FOXI3 were set to Bilateral Microtia; Congenital aural atresia Review for gene: FOXI3 was set to GREEN Added comment: Quiat et al. 2022 (PMID: 36260083) reported 4 unrelated families affected by microtia with or without atresia and different predicted deleterious heterozygous variants in the FOXI3 gene. Variants segregated with disease, including in multiplex families, albeit with reduced penetrance. In vitro studies showed that patient variants conferred abnormal FOXI3 nuclear and cytoplasmic localization. Tassano et al. 2015 (PMID: 25655429) also identified a patient with microtia, aural atresia, and ipsilateral agenesis of the carotid artery who harboured a 2.5 Mb deletion overlapping the FOXI3 gene. Congenital ear malformations with variable penetrance have been described in a Foxi3 knockout mouse model and haploinsufficient canine breeds supporting a role of FOXI3 in the human phenotype (PMID: 18787161; 24650709) Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.105 | TMEM260 |
Eleanor Williams gene: TMEM260 was added gene: TMEM260 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,PAGE DD-Gene2Phenotype Q4_21_rating tags were added to gene: TMEM260. Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM260 were set to 28318500; 34612517 Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.96 | REN | Arina Puzriakova Tag for-review was removed from gene: REN. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.96 | REN | Sarah Leigh commented on gene: REN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.95 | REN |
Arina Puzriakova Source Expert Review Green was added to REN. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.94 | WBP11 | Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.93 | CTU2 |
Ivone Leong gene: CTU2 was added gene: CTU2 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,Expert list Q2_21_rating tags were added to gene: CTU2. Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTU2 were set to 26633546; 27480277; 31301155 Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.89 | PLVAP |
Ivone Leong gene: PLVAP was added gene: PLVAP was added to Paediatric disorders - additional genes. Sources: Literature Q2_21_rating tags were added to gene: PLVAP. 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, OMIM:618183 Review for gene: PLVAP was set to GREEN Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews: "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 Zornitza Stark (Australian Genomics), 5 Jan 2021" "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. Ivone Leong (Genomics England Curator), 12 Apr 2021" After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.83 | WBP11 |
Eleanor Williams gene: WBP11 was added gene: WBP11 was added to Paediatric disorders - additional genes. 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.81 | OTUD5 |
Arina Puzriakova gene: OTUD5 was added gene: OTUD5 was added to Paediatric disorders - additional genes. 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.77 | RINT1 |
Eleanor Williams gene: RINT1 was added gene: RINT1 was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RINT1 were set to 31204009 Phenotypes for gene: RINT1 were set to Infantile liver failure syndrome 3 OMIM:618641; infantile liver failure syndrome 3 MONDO:0032844 Review for gene: RINT1 was set to GREEN Added comment: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype. PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.72 | TSPYL1 |
Eleanor Williams changed review comment from: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM. 3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported. PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state. PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation. PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found: PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control). PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes. Reports where male infertility cases were screened for TSPYL1 variants: PMID: 19463995 - Vinci et al 2009 - screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. 2 heterozygous variants reported. One in a 46,XY female with complete gonadal dysgenesis (p.K320R in the conserved NAP domain) and a 46,XY male with idiopathic azoospermia (p.R89H). PMID: 22137496 - Javaher et al 2012 - screen 104 infertile men for variants in TSPYL1. 2 potentially pathogenic heterozygous variants identified. 1 with azoospermia had a c.419C>G (p.Ser140Cys) variant and 1 with OAT syndrome had the rare c.1098C>A (p.Phe366Leu). However, 1 fertile man was also found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). The authors concluded that TSPYL1 variants did not play a major role in idiopathic male infertility and would not recommend inclusion in diagnostic screening. Sources: Literature; to: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM. 3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported. PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state. PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation. PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found: PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control). PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.72 | TSPYL1 |
Eleanor Williams gene: TSPYL1 was added gene: TSPYL1 was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: TSPYL1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TSPYL1 were set to Sudden infant death with dysgenesis of the testes syndrome OMIM:608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124 Review for gene: TSPYL1 was set to GREEN Added comment: Associated with Sudden infant death with dysgenesis of the testes syndrome #608800 (AR) in OMIM. 3 independent cases with biallelic variants in TSPYL1 in patients with Sudden Infant Death with Dysgenesis of the Testes syndrome reported. PMID: 32885560 - Slater et al 2020 - report a Hispanic, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Mild T-cell lymphopenia, absent uterus and adnexal structures, with no gonads visible and intractable epilepsy are also reported. The patient died of respiratory failure at 8 months of age. Exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52). The variant has a frequency of 0.002% in gnomAD but has not been reported in the homozygous state. PMID: 33075815 - Buyse et al 2020 - report 3 affected siblings from a consanguineous Turkish family. The phenotype was characterized by visceroautonomic dysfunction, severe postnatal progressive neurological abnormalities, visual impairment, testicular dysgenesis in males and sudden death at infant age. WES analysis found a homozygous frameshift variant p.Val242GlufsTer52 in TSPYL1 in the affected siblings. The variant is found in gnomAD at a MAF of 0.0021%, but no homozygous individuals are reported. The parents and one unaffected sibling were heterozygous for the variant. The truncated protein was retained in the Golgi in patient fibroblasts whereas in control fibroblasts the full length protein was found in the nucleus. Patient cells also showed prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depleted zebrafish showed a similar phenotype with early lethality, defects in neurogenesis and cardiac dilation. PMID: 15273283 - Puffenberger et al 2004 - report 21 individuals from a large Old Order Amish kinship with a phenotype of sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males. A homozygous frameshift mutation c.457dupG (p.Glu153Glyfs*17) was detected after autozygosity scanning and sequencing of the the TSPYL (now known as TSPYL1) gene. All parents were heterozygous for the mutation. Functional experiments showed that there was a loss of nuclear localization of truncated TSPYL Two reports where SIDS cases were screened for TSPYL1 variants but only heterozygous variants were found: PMID: 25449952 - Schubert et al 2015 - screened TSPYL1 in 165 SIDS cases with mostly Swiss ethnic origin, and 163 German control adults. 8 known polymorphisms were detected, 3 affected individuals were found to have rare heterozygous missense variants (1 x c.106C>G (p.Leu36Val), 2 x c.1098C>A, p.Phe366Leu). The p.Phe366Leu variants was also found in a control individual. 2 silent rare variants were also found (1 case, 1 control). PMID: 16418600 - Hering et al 2006 - screen TSPYL1 in 126 SIDS cases and 261 controls. Found one female one female patient with a heterozygous p.F366L amino acid polymorphism which was not found in the controls. Concluded that the genetic analysis of TSPYL1 was of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes. Reports where male infertility cases were screened for TSPYL1 variants: PMID: 19463995 - Vinci et al 2009 - screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. 2 heterozygous variants reported. One in a 46,XY female with complete gonadal dysgenesis (p.K320R in the conserved NAP domain) and a 46,XY male with idiopathic azoospermia (p.R89H). PMID: 22137496 - Javaher et al 2012 - screen 104 infertile men for variants in TSPYL1. 2 potentially pathogenic heterozygous variants identified. 1 with azoospermia had a c.419C>G (p.Ser140Cys) variant and 1 with OAT syndrome had the rare c.1098C>A (p.Phe366Leu). However, 1 fertile man was also found to be heterozygous for the rare variant c.487G>A (p.Val163Ile). The authors concluded that TSPYL1 variants did not play a major role in idiopathic male infertility and would not recommend inclusion in diagnostic screening. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.71 | VIM |
Eleanor Williams gene: VIM was added gene: VIM was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: VIM was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: VIM were set to 32066935 Phenotypes for gene: VIM were set to lipodystrophy HP:0009125; Craniofacial dysostosis HP:0004439; Thoracic scoliosis HP:0002943; amyotrophy Review for gene: VIM was set to RED Added comment: Previously variants in this gene have been associated with cataracts (PMID: 26694549, 19126778). Cogne et al 2020 (PMID: 32066935) - report a de novo heterozygous variant in VIM (c.1160 T > C; p.(Leu387Pro)) causing a syndromic disorder affecting craniofacial development, peripheral nervous system, and adipose and ectodermal tissues in a 39 year old male. The variant was identified by WES. Both parents lacked the variant. Expression of human vimentin p.(Leu387Pro) in zebrafish resulted in a phenotype of perturbed body fat distribution, and craniofacial and peripheral nervous system development. Functional studies using patient-derived and transfected cells showed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin. Added gene to this panel on advice from Genomics England Clinical team. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.69 | NHLRC2 |
Eleanor Williams gene: NHLRC2 was added gene: NHLRC2 was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NHLRC2 were set to 29423877; 32435055 Phenotypes for gene: NHLRC2 were set to FINCA syndrome OMIM:618278 Review for gene: NHLRC2 was set to GREEN Added comment: PMID: 29423877 Uusimaa et al 2018 - report 3 patients from 2 unrelated non-consanguineous Finnish families in which the children were born asymptomatic but by 2 months of age they had developed a progressive multi-organ disorder. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. All three patients were found using WES to be compound heterozygous for NM_198514:c.442G>T, p.Asp148Tyr and c.601_602delAG, p.Arg201GlyfsTer6. Segregation data for both families is provided. The family history of the two families, traced back 7–9 generations, showed that they did not have common ancestors. Both variants are rare in both Finnish (Sequencing Initiative Suomi - 0.003 and 0.0001 respectively) and non-Finnish populations (Exac). Patient fibroblasts expressed only mRNA with the c.442G>T missense variant, and at low levels. Development of Nhlrc2 null mice stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos showed that nhlrc2 has a role in cellular integrity of the central nervous system during development. PMID: 32435055 - Brodsky et al 2020 - report a 2 year old Ukranian patient with FINCA syndrome who was found by WES to have compound heterozygous variants in NHLRC2 (c.442T>G, p.D148Y and c.428C>A, p.H143P). The c.428C>A variant is not found in the gnomAD database. Each parent was a carrier for one of the variants. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.64 | PIGQ |
Sarah Leigh commented on gene: PIGQ: Comments from Konstantinos Varvagiannis Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548). Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362). Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality. PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis. More than 10 variants have been reported to date (missense / pLoF). Overall PIGQ can be considered for green rating in both ID and epilepsy gene panels. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.54 | NADSYN1 |
Sarah Leigh gene: NADSYN1 was added gene: NADSYN1 was added to Paediatric disorders - additional genes. Sources: Expert list,Literature Mode of inheritance for gene: NADSYN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NADSYN1 were set to 31883644 Phenotypes for gene: NADSYN1 were set to Vertebral, cardiac, renal, and limb defects syndrome 3 618845 Review for gene: NADSYN1 was set to AMBER Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644). Sources: Expert list, Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.51 | ITGA8 | Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.46 | LRIG2 |
Rebecca Foulger commented on gene: LRIG2: PMID:23313374. Stuart et al., 2013 performed exome sequencing in affected siblings from a consanguineous Turkish family with urofacial syndrome. A 1bp deletion variant resulting in premature termination (Glu140AspfsTer6) was found in an 8 year old girl, but also in her 5 year old brother who exhibited the facial features but not CAKUT phenotype. The variant was found in heterozygosity in the unaffected first-cousin parents. In a second Turkish family with urofacial syndrome, two affected sisters were homozygous for a nonsense LRIG2 variant (R709X). A third case comes from a 5year old Spanish girl compound het for a 1bp deletion (Ser697HisfsTer11) and 371bp insertion variant in LRIG2. Her unaffected parents were each heterozygous for one of the variants. Facial phenotypes of Urofacial syndrome include grimacing on smiling. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.43 | GATA3 | Rebecca Foulger Added comment: Comment on list classification: Updated from Amber to Green awaiting GLH review. GATA3 HDR syndrome includes hypoparathyroidism and sensorineural deafness in addition to renal dysplasia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.42 | GATA3 | Rebecca Foulger commented on gene: GATA3: PMID:11389161. Muroya et al., 2001 report 9 Japanese families with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia). Heterozygous gross deletions were reported by FISH in 4 families. Sequence analysis showed heterozygous novel variants in 3 families. 2 families had no GATA3 abnormalities detected. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.42 | REN | Rebecca Foulger Classified gene: REN as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.42 | REN | Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review as to whether renal phenotypes are sufficient for inclusion on the Paediatric disorders panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.42 | REN | Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.41 | REN | Rebecca Foulger commented on gene: REN: PMID:31736371. He et al., performed a study to identify the potentially pathogenic gene variants that contribute to the AR renal tubular dysgenesis (RTD) in the aborted fetus. WES was performed on an aborted fetus and his parents. Compound heterozygous variants (c.963T>A, p.Y321X and c.492+1G>A splicing site mutation) were identified in the fetus, one inherited from each parent. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.41 | REN | Rebecca Foulger Publications for gene: REN were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.40 | REN | Rebecca Foulger Added comment: Comment on mode of inheritance: Hyperuricemic nephropathy, familial juvenile 2, 613092 has AD inheritance, and Renal tubular dysgenesis, 267430 has AR inheritance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.40 | REN | Rebecca Foulger Mode of inheritance for gene: REN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.39 | REN | Rebecca Foulger Phenotypes for gene: REN were changed from CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis to CAKUT; [Hyperproreninemia]; Hyperuricemic nephropathy, familial juvenile 2, 613092; Renal tubular dysgenesis, 267430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.37 | GREB1L | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green awaiting GLH review: although the predominant phenotype is renal defects, inner ear malformations are also included in the phenotypic spectrum (PMID:29955957). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.36 | GREB1L | Rebecca Foulger Phenotypes for gene: GREB1L were changed from CAKUT; Renal hypodysplasia/aplasia 3, 617805 to CAKUT; Renal hypodysplasia/aplasia 3, 617805; inner ear malformations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.34 | GREB1L | Rebecca Foulger commented on gene: GREB1L: PMID:29261186 (Boissel et al., 2018) performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies. In 2 cases who presented with renal agenesis, de novo variants in GREB1L were identified (p.A968V and p.S98X). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.32 | CHRNA3 | Rebecca Foulger changed review comment from: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.; to: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA3 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.32 | AGTR1 | Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now. Plenty of literature suggesting links between AGTR1 polymorphisms and disease risk for e.g. pulmonary arterial hypertension (e.g. PMID:25603901) but key congenital disorder seems to be renal dysgenesis (PMID:16116425). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.31 | AGTR1 | Rebecca Foulger commented on gene: AGTR1: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.30 | ANOS1 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green, awaiting GLH review. Sufficient cases to support Kallman syndrome association, which can present with phenotypes beyond renal, some of which could be detected at birth. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.29 | ANOS1 | Rebecca Foulger commented on gene: ANOS1: PMID:16423815. Trarbach et al 2005 report 12 Kallmann syndrome (KS) patients. Two ANOS1 variants (referred to as KAL-1 gene) were found in 2 KS patients (Arg191X, and del1956C leading to a premature stop codon at 617). A patient with a KAL-1 microdeletion was also reported. Renal agenesis and bimanual synkinesis were observed in these cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.27 | AGT | Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now: renal tubulogenesis is key phenotype and therefore CAKUT may be isolated. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.25 | ACTG2 | Rebecca Foulger changed review comment from: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).; to: PMID:27481187 Moreno et al., 2016. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.25 | ACTG2 | Rebecca Foulger commented on gene: ACTG2: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.24 | ACTG2 | Rebecca Foulger changed review comment from: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK.; to: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMIHS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMIHS (MIM:249210) is associated with MYLK. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.24 | ACE | Rebecca Foulger Added comment: Comment on list classification: Key papers report renal tubular dysgenesis. In absence of additional morphological features, keep Amber awaiting GLH review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.23 | ACE | Rebecca Foulger commented on gene: ACE: PMID:30058238 (Bhowmik et al., 2018) report a 32-week old fetus with severe early onset oligohydramnios. A similarly affected sibling was reported from a previous pregnancy. Exome sequencing revealed a homozygous 3' splice-site variant in intron 17 of ACE gene, which confirmed AR renal tubular dysgenesis. It also facilitated prenatal diagnosis in a subsequent pregnancy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.23 | ACE | Rebecca Foulger commented on gene: ACE: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.22 | CHRNA3 | Rebecca Foulger commented on gene: CHRNA3: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.22 | ANOS1 | Rebecca Foulger changed review comment from: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.; to: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.21 | ANOS1 | Rebecca Foulger commented on gene: ANOS1: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.21 | AGT | Rebecca Foulger commented on gene: AGT: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.21 | AGT | Rebecca Foulger Phenotypes for gene: AGT were changed from CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis to Renal tubular dysgenesis, 267430; CAKUT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.19 | ACTG2 | Rebecca Foulger commented on gene: ACTG2: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.15 | REN | Rebecca Foulger Classified gene: REN as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.15 | REN | Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.4 | REN | Rebecca Foulger Tag for-review tag was added to gene: REN. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.4 | REN | Rebecca Foulger commented on gene: REN: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.4 | REN | Rebecca Foulger commented on gene: REN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | AGT |
Rebecca Foulger gene: AGT was added gene: AGT was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AGT were set to CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | ITGA8 |
Rebecca Foulger gene: ITGA8 was added gene: ITGA8 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: ITGA8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITGA8 were set to CAKUT; Renal hypodysplasia/aplasia 1, 191830 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | GATA3 |
Rebecca Foulger gene: GATA3 was added gene: GATA3 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: GATA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: GATA3 were set to CAKUT; Hypoparathyroidism, sensorineural deafness, and renal dysplasia, 146255; Hypoparathyroidism, Sensorineural Deafness, and Renal Disease |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | REN |
Rebecca Foulger gene: REN was added gene: REN was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: REN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: REN were set to CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | GREB1L |
Rebecca Foulger gene: GREB1L was added gene: GREB1L was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GREB1L were set to 29100091; 29220675 Phenotypes for gene: GREB1L were set to CAKUT; Renal hypodysplasia/aplasia 3, 617805 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | AGTR1 |
Rebecca Foulger gene: AGTR1 was added gene: AGTR1 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AGTR1 were set to CAKUT; Hypertension, essential, 145500; Renal Tubular Dysgenesis; Renal tubular dysgenesis, 267430 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v1.3 | ACE |
Rebecca Foulger gene: ACE was added gene: ACE was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACE were set to CAKUT; Renal Tubular Dysgenesis |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.35 | STK4 | Ellen McDonagh reviewed gene: STK4: Rating: AMBER; Mode of pathogenicity: ; Publications: 22294732, 22174160; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.34 | STK4 |
Ellen McDonagh gene: STK4 was added gene: STK4 was added to Paediatric disorders - additional genes. Sources: South West GLH Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STK4 were set to 22294732; 22174160 Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.33 | SOX11 | Rebecca Foulger commented on gene: SOX11: Alisdair McNeill (Sheffield Childrens Hospital) review, copied from DDG2P Panel Version: 1.128, Created: 7 Oct 2019, 2:38 p.m.: I have identified a series (unpublished) of around 20 children with de novo variants in SOX11 and overlapping clinical features. I think this is a real, though rare, cause of neurodevelopmental disorders. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.31 | SOX11 |
Rebecca Foulger gene: SOX11 was added gene: SOX11 was added to Paediatric disorders - additional genes. Sources: Expert list Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SOX11 were set to MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27; Coffin-Siris syndrome 9, 615866 Added comment: Added SOX11 to the panel based on a Green review left by Alisdair McNeill (Sheffield Childrens Hospital) for SOX11 on the PanelApp DDG2P panel. SOX11 currently has a probable Disease confidence in Gene2Phenotype for MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27, but Alisdair McNeil's review provides sufficient cases for a Green rating on the Paediatric disorders Super panel. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.23 | ABL1 |
Helen Brittain gene: ABL1 was added gene: ABL1 was added to Paediatric disorders - additional genes. Sources: Literature missense tags were added to gene: ABL1. Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ABL1 were set to 28288113 Phenotypes for gene: ABL1 were set to Congenital heart defects and skeletal malformations syndrome 617602 Penetrance for gene: ABL1 were set to unknown Mode of pathogenicity for gene: ABL1 was set to Other Review for gene: ABL1 was set to GREEN Added comment: "4 unrelated families who exhibited dysmorphic facial features, congenital heart disease, skeletal abnormalities, joint problems, failure to thrive, gastrointestinal problems, and male genital anomalies. In younger children, dysmorphic features included broad forehead, small nose, deep-set eyes, and small chin, whereas in older patients, the face appeared elongated, with a narrow maxilla, long and narrow nose, and pointed chin. Common skeletal abnormalities included pectus excavatum, scoliosis, finger contractures, and hindfoot deformity. Congenital heart defects included atrial and ventricular septal defects, and in older patients, aortic root dilation." Sufficient cases for a green rating. Note that two missense variants have been reported to date - unclear on mode of pathogenicity. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.21 | IARS | Rebecca Foulger commented on gene: IARS: DD-G2P Disease confidence rating of 'probable' for 'Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy', but sufficient cases from the literature to support Green rating. As reviewed by Louise Daugherty on the 'Intellectual disability' panel: Kopajtich et al., 2016 PMID:27426735 reported 3 unrelated patients with a multisystem disorder characterized by intrauterine and postnatal growth retardation, including small head circumference (-3 to -5 SD), hypotonia and delayed psychomotor development with variable severity of intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.15 | ASCC1 | Rebecca Foulger Added comment: Comment on list classification: Updated rating of ASCC1 on the 'Paediatric disorders - additional genes' panel from Red to Green based on the review Julia Baptista left on the 'DDG2P' panel and the 'Fetal anomalies' panel. ASCC1 was originally Red on the DDG2P panel based on a Gene2Phenotype Disease confidence rating of 'possible' for: Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures (MOI: biallelic). There are sufficient cases to support inclusion as a Green paediatric gene as per Julia Baptista's review. ASCC1 is already Green on the Fetal anomalies panel, and the Arthrogryposis panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.14 | ASCC1 | Rebecca Foulger Phenotypes for gene: ASCC1 were changed from Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures to Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures; spinal muscular atrophy; arthrogryposis; fetal akinesia; hypotonia; contractures | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v0.11 | ASCC1 |
Rebecca Foulger gene: ASCC1 was added gene: ASCC1 was added to Paediatric disorders - additional genes. Sources: Expert Review Red Mode of inheritance for gene: ASCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASCC1 were set to 26924529 Phenotypes for gene: ASCC1 were set to Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||