34
Case34: 3.5 wks (at biopsy), White/Hispanic
Case 34 (Level 2)
CasePreviousTesting: same as group. found 1.6 nmol/mg protein/18 h propionate incorporation, 1.8 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)
ClinVar: 1887
CAID: CA249732
gnomAD: 0.0008393 (Latino)
CaseAddInfo: mut0 type, homozygous mutations.
Table 2
Case1b: Female, Algeria
CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0001622 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Preterm delivery)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001627 (Cardiac abnormality)
NotHPOsFreeText: N/A
CaseAddInfo: Severe congenital myopathy, Deceased in neonatal period, Parents are consanguineous
CasePreviousTesting: N/A
CaseGenotypingMethod: Linkage analysis combined with homozygosity mapping was used to identify candidate chromosomal loci. Whole exome sequencing in this family revealed likely pathogenic mutations in LMOD3 which agreed with the aforementioned analysis and was consistent with autosomal recessive inheritance.
Variant: NM_198271.4(LMOD3):c.138dup (p.Ser47Glnfs)
ClinVar: 162215 https://www.ncbi.nlm.nih.gov/clinvar/variation/162215/
gnomAD: European (Non-Finnish) 8.879e-6, Overall 8.049e-6 https://gnomad.broadinstitute.org/variant/3-69171399-T-TG
P4
Case4: Male, Chinese, 2.8 y (end of study)
HPOsFreeText: poor neurologic outcome, neonatal onset
NotHPOsFreeText: not responsive to vitamin B12
Case4 (Level 2):
CasePreviousTesting: NBS
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)
ClinVar: 552079
CAID: CA3847064
gnomAD: 0.0002008 (East Asian)
CaseAddInfo: homozygous mutations
P5
Case5: Female, Chinese, 1.6 y (onset)
HPOsFreeText: 1.6 y onset
NotHPOsFreeText: Not responsive to vitamin B12
Case5 (Level 2):
CasePreviousTesting: same as group
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_000255.3:c.1106G>A (p.Arg369His)
ClinVar: 203846
CAID: CA312764
gnomAD: 0.0001504 (East Asian)
CaseAddInfo: homozygous mutations, lost to follow up
P3
Case3: Female, Chinese, 4 mo (end of study)
HPOsFreeText: Responsive to vitamin B12
Case3 (Level 2):
CasePreviousTesting: NBS
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_000255.3:c.599T>C (p.Ille200Thr)
ClinVar: n/a
CAID: CA364404381
gnomAD: n/a
CaseAddInfo: homozygous mutations, asymptomatic
P2
Case2: Male, Chinese, 3 mo (age at death)
HPOsFreeText: Neonatal onset
NotHPOsFreeText: Not responsive to vitamin B12
Case2 (Level 2):
CasePreviousTesting: NBS (newborn screening)
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_000255.3:c.482G>T (p.Gly161Val)
ClinVar: n/a
CAID: CA364404636
gnomAD: n/a
CaseAddInfo: homozygous mutations, novel mutation
3
CaseCA3: Male, 6 months diagnosis
CasePresentingHPOs: HP:0001644, HP:0001875, HP:0001508, HP:0003535, HP:0003756, HP:0030319, HP:0003551 (Dilated cardiomyopathy, Neutropenia, Failure to thrive, 3-Methylglutaconic aciduria, Skeletal myopathy, Facial weakness, Difficulty climbing stairs)
HPOsFreeText: N/A
CaseNotHPOs: HP:0003107 (Abnormal circulating cholesterol concentration)
NotHPOsFreeText: N/A
CaseAddInfo: Cardiac transplant 11 months after presentation; Variant also found in mother and grandmother
CasePreviousTesting: N/A
CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in the mother and proband.
Variant: NM_000116.5(TAZ):c.589G>A (p.Gly197Arg)
ClinVar: 11105, https://www.ncbi.nlm.nih.gov/clinvar/variation/11105/
gnomAD: Not in gnomAD
We evaluated 16 patients with IVA, including 3 pairs of siblings
Patient5: Male, 11mo, sibling to patient 4
CasePresentingHPOs:
HPOsFreeText: Asymptomatic, C5 (DBS) = 6.0 μmol l−1, IVA incorp (%) = 64, IVG in urine mmol permol creatinine = 955, Ammonium (μmol l−1) = 65, pH = 7.41, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 85
CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259
(poor feeding, vomiting, dehydration, lethargy, coma)
NotHPOsFreeText: sweaty feet odor
CaseAddInfo: Diagnosed with NBS at 10 days old
CasePMIDs:
CasePreviousTesting: same as group
CaseGenotypingMethod: same as group
Variant1: NM_001159508.1:c.1214T>C
CAID: CA268781818, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781818
gnomAD: 0.000003977, http://gnomad.broadinstitute.org/variant/15-40710485-T-C
Variant2: NM_001159508.1:c.500T>C
CAID: CA391717541, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391717541
gnomAD: n/a
Subject A
CaseGuA: Male, 6 weeks onset
CasePresentingHPOs: HP:0200134, HP:0020217, HP:0002069, HP:0010852, HP:0012012, HP:0012017, HP:0012018, HP:0010841, HP:0025152, HP:0030211, HP:0008936, HP:0002061, HP:0006986, HP:0002187, HP:0011344, HP:0001344, HP:0012448, HP:0002283, HP:0002079, HP:0012696, HP:0002500, HP:0012751 (Epileptic encephalopathy, Focal aware motor seizure, Bilateral tonic-clonic seizure, EEG with parietal focal spike waves, EEG with parietal focal spikes, EEG with temporal focal spikes, Multifocal epileptiform discharges, Poor visual behavior for age, Slow pupillary light response, Muscular hypotonia of the trunk, Lower limb spasticity, Upper limb spasticity, Profound intellectual disability, Severe global developmental delay, Absent speech, Delayed myelination, Global brain atrophy, Thin corpus callosum, Abnormal thalamic MRI signal intensity, White matter abnormalities, Abnormal basal ganglia MRI signal intensity)
HPOsFreeText: Dyskinetic movements of arms, In ability to sit unsupported, Abnormal MRI signal in putamen and caudate
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Variant is confirmed heterozygous de novo
CasePreviousTesting: Investigations include electroencephalography (EEG), head MRI, neurometabolic testing, and chromosome microarray; Individuals with self-limiting benign electroclinical syndromes, such as childhood absence epilepsy (onset > 4 years), were excluded; Capture of right arm jerks and chin twitching showed no EEG correlate; Head circumference was 45.1 cm at 8 months (50%), 52 cm at 5 years (50th percentile); Partial response to phenobarbital, levetiracetam, and clobazam; Longest seizure-free period was 16 months
CaseGenotypingMethod: Variants within co-expressed candidate genes in Table S1 were extracted from exome sequencing data. Variants were annotated and were verified with Sanger sequencing of the proband and parents.
Variant: NM_004171.4(SLC1A2):c.244G>A (p.Gly82Arg)
ClinVar: 438736, https://www.ncbi.nlm.nih.gov/clinvar/variation/438736/
gnomAD: Not in gnomAD
Patient 1
CaseSA1: Male, Serbia
CasePresentingHPOs: HP:0025190, HP:0001987, HP:0000825, HP:0001988, HP:0001252, HP:0025502, HP:0001263 (Generalized tonic-clonic seizure, Hyperammonemia, Hyperinsulinemic hypoglycemia, Recurrent hypoglycemia, Muscular hypotonia, Overweight, Global developmental delay)
HPOsFreeText: Born at term with a birth weight of 3850 g, birth length of 51 cm, and an Apgar score of 10
CaseNotHPOs: HP:0002353 (EEG abnormality)
NotHPOsFreeText: N/A
CaseAddInfo: Parents are healthy and non-consanguineous with no family history,
CasePreviousTesting: At 9 weeks blood glucose at 2.0 mmol/L, serum insulin level of 32.4 mIU/L, plasma ammonia level was of 277 μmol/L; No abnormalities in plasma amino acid levels nor in urinary organic acid concentrations
CaseGenotypingMethod: Genetic analysis was perfomed on the GLUD1 gene.
Variant: NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)
ClinVar: 16122, https://www.ncbi.nlm.nih.gov/clinvar/variation/16122/
gnomAD: Not in gnomAD
Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia
PMID: 18241071
Gene: PAX6
Variant NM_001368894.2:c.-128-2del
Disease: Ocular dysgenesis
InheritancePattern: AD
Disease PAX6-related ocular dysgenesis MONDO:0800183
The clinical application of a new, widely applicable method known as Karyomapping to carry out a total of 55 clinical cases of preimplantation genetic diagnosis (PGD) for single gene disorders is reported.
Unable to annotate on article.
Case#: Konstantinidis Case 2
DiseaseAssertion: optic atrophy
FamilyInfo: none provided
CasePresentingHPOs: none, tests performed on blastocyst
CaseHPOFreeText:
CaseNotHPOs: none
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.182A > G
ClinVar: 511815
CAID: CA2758946
SupplementalData: n/a
II:5. A 66-year-old woman had had visual impairment since childhood and had attended a special school for the blind. She presented with a further slowly progressive deterioration in her visual acuity, a progressive gait disturbance of 20 years duration, and a 5-year history of deteriorating hearing. Shortly after presentation she developed acute paranoid delusions, low mood and visual hallucinations which resolved spontaneously. On examination, she was just able to perceive light and had bilateral optic atrophy. There was a complete external ophthalmoplegia, bilateral ptosis and bifacial weakness. Her gait was ataxic, tendon reflexes depressed and plantar responses flexor. Clinical investigations revealed an elevated serum creatine kinase (417 U/l, normal <190 U/l) with a normal fasting blood glucose and lactate. An electrocardiogram showed left axis deviation but an echocardiogram was normal. A chest X-ray and pulmonary function tests were normal. An EEG revealed evidence of a mild cortical disturbance. Brain MRI revealed mild cortical and cerebellar atrophy, and prominent small-vessel ischaemic lesions in the cerebral white matter bilaterally.
Case#: Hudson Proband II:5, 66yo, female, UK
DiseaseAssertion: OA plus
FamilyInfo: Pedigree (Fig 1) shows 6 segregations
CasePresentingHPOs: HP:0007663, HP:0001288, HP:0001730, HP:0000746, HP:0002367, HP:0000648, HP:0000544, HP:0001488, HP:0001349, HP:0002066, HP:0001315, HP:0003236, HP:0033568, HP:0001272, HP:0002120
CaseHPOFreeText: slowly progressive deterioration in her visual acuity, a progressive gait disturbance of 20 years duration, and a 5-year history of deteriorating hearing, acute paranoid delusions, low mood, just able to perceive light, bilateral optic atrophy, plantar responses flexor, elevated serum creatine kinase (417 U/l, normal <190 U/l) with a normal fasting blood glucose and lactate, mild cortical disturbance, prominent small-vessel ischaemic lesions in the cerebral white matter bilaterally. Muscle biopsy of the index case (II:5) revealed features that were diagnostic of mitochondrial myopathy
CaseNotHPOs: HP:0001627, HP:0031983
CaseNotHPOFreeText:
PreviouslyPublished: n/a
PreviousTesting: The entire mitochondrial genome-coding region was amplified and found (m.8839G>A) in the MTATP6 gene. No sequence variants were identified in the coding region or flanking exon–intron boundaries for POLG1, PEO1, POLG2 and SLC25A4.
GenotypingMethod: The 30 coding exons and intron–exon junctions of the OPA1 gene were sequenced using a set of 30 primer pairs
Variant: c.1800C>G (p.Ser600Arg)
ClinVar: 30461
CAID: CA10575554
SupplementalData:
The proband, a 47-year-old male (III:15; Fig. 1), was referred for evaluation due to obvious chest tightness and was diagnosed with HCM at 37 years of age
Proband III:15, 47 yr old male, Dx = 37 yrs
HP:0001639, HP:0001681
HCM, chest tightness (angina)
Variant: NM_016599.4(MYOZ2):c.505A>C (p.L169G)
Not in ClinVar or EXAC
Extension of the mutation spectrum of PAX6 from three Chinese congenital aniridia families and identification of male gonadal mosaicism
PMID: 30334364
Variant NM_000280.5:c.1123C>A (p.Pro375Thr)
Gene: PAX6
Disease: Ocular dysgenesis
InheritancePattern: AD
Patient 2
Case2: Female, Austria, 18 yrs report
CasePresentingHPOs: HP:0010628, HP:0002643, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0001511, HP:0001561, HP:0005216, HP:0002540, HP:0002650 (Facial weakness, Neonatal respiratory distress, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Intrauterine growth restriction, Polyhydramnios, Chewing difficulties, Non-ambulatory, Scoliosis)
HPOsFreeText: 3/3/5 Apgar score
CaseNotHPOs: HP:0002015 (Swallowing difficulties)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: Whole exome sequencing of the proband revealed these homozygous LMOD3 mutations.
Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)
ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/
gnomAD: Not in gnomAD
Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)
ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/
gnomAD: Not in gnomAD
Patients 3
Case3: Male, Germany, 20 yrs report
CasePresentingHPOs: HP:0010628, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0002650 (Facial weakness, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Scoliosis)
HPOsFreeText: 7/8/9 Apgar score
CaseNotHPOs: HP:0002015, HP:0002540, , HP:0002098 (Swallowing difficulties, Non-ambulatory, Respiratory distress)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: Next generation sequnecing-based panel analysis detected the below variants in LMOD3.
Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)
ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/
gnomAD: Not in gnomAD
Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)
ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/
gnomAD: Not in gnomAD
All nine affected individuals presented with various skeletal dysplasias. In four families (A and C–E), X-rays revealed severe platyspondyly leading to disproportionate stature (Figure 1). Lumbar gibbus and kyphoscoliosis were observed in families C and D, respectively. Three individuals (from families D and E) had cervical malformations and a hypoplastic odontoid peg with cervical instability. Short stature was also present in families A and B but appeared to be the result of limb shortening. Metaphyseal abnormalities of the long bones were found in families A and E, whereas families B–D showed epiphyseal abnormalities (Figure 1). Brachydactyly was observed in affected individuals from families A, B, and D. In addition to showing skeletal abnormalities, all affected individuals in families B and C had intellectual disability (ID). This could not be assessed for individuals A:II-1, E:II-1, and E:II-2 because of their early death at 7 weeks, 6 months, and 10 months of age, respectively. Both siblings of family B were severely disabled and unable to speak and are currently wheelchair bound. Dysmorphic facial features were non-discriminatingly mild but included coarse facial features, a prominent nose, and full cheeks in almost all affected individuals (Figure S1). A single palmar crease was also observed in six of nine affected individuals. A striking phenotype present in three of the five families was T-cell-negative SCID. Affected individuals from families A and B showed a lack of T cells, whereas B cell numbers were normal (Figure 4). Family E showed idiopathic CD4+ lymphopenia and an absolute lack of naive T cells (both CD4+CD45RA+ and CD8+CD45RA+ T cells were missing). In families B and E, a typical skin rash prompted further evaluation of the blood cells. Maternal T cells were excluded, and the oligoclonal T cell reaction found in the presence of eosinophilia was compatible with an Omenn-like presentation of SCID.1,2 Worth mentioning are also the liver cysts seen in affected individuals from families A and E. Although the phenotypes were widely variable and partly contrasting (e.g., severe versus no ID, severe versus mild platyspondyly, and epiphyseal versus metaphyseal changes), all major malformations and features occurred in three organ systems only: the immune system, the skeleton, and the neurological system. All together, we classify these five families as having phenotypic variability of an EXTL3-related neuro-immuno-skeletal dysplasia phenotype. The affected individuals from families A and E died in early infancy, whereas the others are currently between 2 and 38 years of age. Individual III-1 from family D died at 30 years of age from a unknown cause. Table 1 gives an overview of the most affected organ systems in all affected individuals. Detailed case reports and clinical data for each affected individual can be found in the Supplemental Note.
Case 1: Family A: AII-1, female
Born at 37 weeks, consanguineous family, APGAR = 9, tachypnea developed shortly after birth. At 20 weeks, skeletal abnormalities and kidney and liver cysts were detected. Died at 7 weeks from renal insufficiency.
HPO Terms: HP:0002652, HP:0001999, HP:0002789, HP:0005562, HP:0001407, HP:0009826, HP:0000926, HP:0001156, HP:0000085, HP:0000083, HP:0002079, HP:0002119, HP:0030747, HP:0011839
Previous Testing: Found autosomal recessive variant in CHST9 (MIM: 610191; c.1133A>G [p.Asn378Ser] [GenBank: NM_031422])
Genotyping Method: WES, CNV performed on WES data, EXTL3 fibroblast localization tested and compared to non-affected controls using immunocytochemistry
Variant: p.Arg513Cys, g.28575113, c.1537C>T
ClinVar ID: n/a
gnomAD: http://gnomad.broadinstitute.org/variant/8-28575113-C-T
Inheritance: autosomal recessive
Variant Evidence:
Case 3
Case#: 3, female, 12 days (onset), 4 y (current- this differs than what is in table 1), Chinese
CasePresentingHPOs: HP: 0008344, HP: 0012088, HP:0011968, HP: 0002013, HP:0011344, HP: 0002543, HP: 0012751 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, vomiting, severe global developmental delay, abnormal globus pallidus, abnormal basal ganglia)
HPOsFreeText: Bilateral damage to capsula interna and externa, Blood ammonia: 205 uM, Hemoglobin: 118 g/L, Leucin: 891.90 uM, Valine: 502.50 uM, Isoleucine: 165.99 uM, Alloisoleucine: 90.12 uM
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 2 different variants, unsure of cis or trans
CasePreviousTesting: n/a
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_000709.3(BCKDHA):c.178G>T (p.Glu60Ter), NM_000709.3(BCKDHA):c.1214_1219dupCCAACC (p.Asn406Leu407insProGln)
ClinVar: n/a
CAID: CA406004676 , CA658820662
gnomAD: neither in gnomAD
Case 6
Case#: 6, male, 18 m (onset), 2 y 6 m (current), Chinese
CasePresentingHPOs: HP: 0008344, HP; 0012088, HP: 0011342, HP: 0001332, HP:0002543, HP: 0012751, HP:0012747 (elevated A keto acids in urine, abnormal urinary odor, mild global developmental delay, dystonia, abnormal globus pallidus, abnormal basal ganglia, abnormal brainstem MRI signal intensity)
HPOsFreeText: damage to cerebellar dentate nucleus, damage to corpora quadrigemina, damage to frontal lobe, damage to insular cortex, Isoleucine: 167.13 uM, Alloisoleucine: 44.88 uM
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: unsure cis or trans
CasePreviousTesting: same as group
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_183050.3:c.767A>G (p.Tyr256Cys), NM_183050.3:c.768C>G (p.Tyr256Ter)
ClinVar: neither found
CAID: CA364659935, CA142287564
gnomAD: 0.000008820 (European, non-Finnish), not found
Case 8
Case#: 8, male, 13 days (onset), 1 y 6 m (current), Chinese
CasePresentingHPOs: HP: 0008344, HP:0012088, HP:0011968, HP:0001254, HP:0002415, HP: 0006989 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, lethargy, leukodystrophy, dysplastic corpus callosum)
FreeTextHPOs: blood ammonia: 96 uM, hemoglobin: 98 g/L, leucin: 1047.24 uM, isoleucine: 261.09 uM, alloisoleucine: 127.05 uM
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: homozygous mutation
CasePreviousTesting: same as group
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant: NM_001918.3:c.1A>G (p.Met1Val)
ClinVar: not found
CAID: CA969877
gnomAD: not found
Case 1
Case#: 1, male, 3 days (onset), 2 y 8 mo (current), Chinese
CasePresentingHPOs: HP:0008344 HP: 0012088, HP: 0001250, HP: 0011968, HP: 0001941, HP: 0001943, HP: 0001987, HP: 0001903, HP:0012751, HP:0002543, HP: 0001276, HP:0011343 (elevated A keto acids in urine, abnormal urinary odor, seizures, feeding difficulties, acidosis, hypoglycemia, hyperammonemia, anemia, abnormal basal ganglia MRI signal intensity, abnormal globus pallidus signals, hypertonia, moderate global developmental delay)
HPOsFreeText: Blood ammonia: 75 uM, Valine: 532.83 uM, Isoleucine: 384.90 uM, Alloisoleucine: 213.09 uM
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: variants also found in parents
Case (Level 2)
CasePreviousTesting: same as group
CaseMethod1: same as group
CaseMethod2: same as group
CaseGenotypingMethod: same as group
Variant1: NM_000709.3(BCKDHA): IVS6+1delG (can't search this format of an intronic mutations, how do I change it?)
ClinVar: not sure how to search for BCKDHA IVS6 + 1delG
CAID:
gnomAD:
Variant2: NM_000709.3(BCKDHA):c.740A>G (p.His247Arg)
ClinVar: not found
CAID: CA406012849
gnomAD: not in gnomAD
There are two variants listed for every patient except, one. The text said that all the mutations found were also found in the parents so does that mean they would be in trans?
(didn't see this template at first, so still need to apply it to the other entries)
VI-4 Son
CaseVI-4: Male, 3.5 years, Turkey
CasePresentingHPOs: HP:0004912, HP:0002540, HP:0002970 (Hypophosphatemic rickets, Inability to walk, Genu varum)
HPOsFreeText: -3.76 standard deviation score
CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)
NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2
CaseAddInfo: Variant is asserted de novo and confirmed by parental testing, Proband is hemizygous for this mutation
CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.8 mg/dL; reference 3.8-6.5), Elevated serum ALP (925 IU/L; reference 90-325), 25OHD3 levels (35 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (62.2 ng/L), TPR levels (69.7), Decreased TmP/GFR levels (1.95; reference 2.9-6.1)
CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.
Variant: NM_000444.5:c.1217G>T (p.Cys406Phe)
CAID: CA412573391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.1217G%3ET
gnomAD: Not in gnomAD
We prospectively recruited 40 patients with confirmed pathogenic OPA1 mutations from our neuro-ophthalmology clinic: 26 patients with isolated optic atrophy and 14 patients manifesting DOA+ features (Table 1). The clinical and molecular descriptions of these patients have been detailed previously.5,9 Best-corrected visual acuity was measured using the Snellen chart and converted to logarithm of the minimum angle of resolution (LogMAR) decimal values for the purpose of statistical analysis.20 The peripapillary RNFL profile in our DOA cohort was compared with age-matched normal controls recruited among members of staff of our eye unit (N=15), and the normative database (N=328) included in the Stratus OCT operating software (Carl Zeiss Meditec, Dublin, CA, USA;
3 individuals with this variant, but they are previously reported. PMIDs: 20417570, 20157015
Patient 1
Case1: Male, 3 months onset, Australia
CasePresentingHPOs: HP:0002878, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0003691, HP:0003391, HP:0003803, HP:0003755 (Respiratory failure, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Scapular winging, Gowers sign, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)
HPOsFreeText: BiPAP from 3.5 yrs, Type 2B fibers absent
CaseNotHPOs: HP:0003798, HP:0030177, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Internally nucleated skeletal muscle fibers)
NotHPOsFreeText: N/A
CaseAddInfo: Variant is de novo with parental testing confirmed
CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.
CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.
Variant: NM_152263.4(TPM3):c.733A>G (p.Arg245Gly)
ClinVar: 42117 https://www.ncbi.nlm.nih.gov/clinvar/variation/42117/
gnomAD: Not in gnomAD
Patient 2
Case2: Male, Birth onset, Australia
CasePresentingHPOs: HP:0008947, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0010628, HP:0003391, HP:0002942, HP:0003803, HP:0003755 (Infantile muscular hypotonia, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Gowers sign, Thoracic kyphosis, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)
HPOsFreeText: Type 2B fibers absent
CaseNotHPOs: HP:0003798, HP:0030177, HP:0030877, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Obstructive deficit on pulmonary function testing, Internally nucleated skeletal muscle fibers)
NotHPOsFreeText: N/A
CaseAddInfo: Variant is de novo with parental testing confirmation
CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.
CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.
Variant: NM_152263.4(TPM3):c.505A>G (p.Lys169Glu)
ClinVar: 42115 https://www.ncbi.nlm.nih.gov/clinvar/variation/42115/
gnomAD: Not in gnomAD
The impact of the substitutions in exon 3’s last nucleotide (position c.550) on splicing was previously functionally evaluated using RNA analysis and was established as pathogenic [75]. In the same splice site, we detected a novel variant, c.550 + 3A > C, in a patient P02201 and as the variant had not been previously reported, we tried to functionally evaluate it. Unfortunately, none of the patient’s family members were available for testing. The variant potentially affecting the donor splice site (5'ss) of exon 3 was analyzed in silico by MaxEnt Score [76], and the ratio between mutated and wild-type 5'ss sequence was 0.41—a number suggesting a substantial effect on splicing. According to Le Guédard-Méreuze et al. [77], substitution + 3A > C is prone to cause a splicing defect even if the donor splice site does not contain any further nucleotide changes. We performed minigene analysis (detailed procedure described in Supplement Methods) to confirm the deleterious effect on splicing and it showed aberrant splicing in nearly 100% of mutated minigene construct transcripts (Fig. 3).Fig. 3Minigene splicing analysis of a novel variant c.550 + 3A > C. The wild-type and mutant genomic fragments of SERPING1 comprising exon 3 and flanking upstream (229 bp) and downstream (255 bp) intron sequences, were cloned into pET01 vector and HepG2 cells were transfected with these minigenes. Capillary electrophoresis of RT-PCR products showed aberrant splicing in nearly 100% of mutated minigene construct transcripts. Several different aberrant transcripts were detected. The most abundant was intron 3 retention followed by exon 3 skipping. Transcripts using cryptic donor splice sites − 10 and + 27 were found in the mutant minigene analysis, whereas they were not detected in the wild type at all. a Minigene analysis results: column A shows transcript proportions resulting from control minigene construct representing c.550 + 3A; column C shows transcript proportions resulting from minigene construct representing c.550 + 3C. b Scheme of the transcripts detected in the minigene analysis. c Scheme of the pET minigene construct. Cryptic splice sites found in the analysis and their exact sequences are displayed. MaxEnt Score values (MES) are specified beneath each splice siteFull size imageVariant c.686-7C > G was detected in a mother and her daughter (P03001-P03002), both affected with HAE symptoms. This variant had been described before [7], but its impact had not been yet fully evaluated. Therefore, we extracted RNA from both patients’ blood and analyzed samples by RT-PCR and fragment analysis (Supplementary Methods), which showed complete impairment caused by the variant (Fig. 4).Fig. 4mRNA analysis of patients carrying variant c.686-7C > G. Capillary electrophoresis was performed on PCR products amplified by primers annealing to exons 4 and 7. a Healthy control shows only one wild type peak. b Both patient sample results show 2 peaks—reference transcript peak and a peak corresponding to a 6 bp longer transcript using a de novo created acceptor splice site. Aberrant and normal transcript proportion was roughly equal, which corresponds to complete impairment caused by the variant. The variant preserves a reading frame and leads to incorporation of additional two amino acids (proline-alanine) into the polypeptide chain
550+3A>C: Minigene analysis showed aberrant splicing in nearly 100% of mutated minigene construct transcripts, confirmed exon 3 splicing disruption
686-7C>G: RT-PCR and fragment analysis. Both patient sample results show 2 peaks (WT shows only 1)—reference transcript peak and a peak corresponding to a 6 bp longer transcript using a de novo created acceptor splice site. Aberrant and normal transcript proportion was roughly equal, which corresponds to complete impairment caused by the variant. The variant preserves a reading frame and leads to incorporation of additional two amino acids (proline-alanine) into the polypeptide chain
Variants: c.550+3A>C; c.686-7C>G
CAIDs: CA2573332696;
A new PAX6 mutation in familial aniridia
PMID: 7666404
Variant NM_001368894.2:c.1225G>C(p.Gly409Arg)
Gene: PAX6
Disease: Ocular dysgenesis
InheritancePattern: AD
Notes SNP at last nucleotide in exon 13 leads to loss of donor site and exon skipping event.
Download : Download high-res image (1MB)Download : Download full-size imageFig. 3. Mutated forms of fusion genes modify the shape of the mitochondrial network. Skin fibroblasts from patients with dominant mutations: MFN2:p.R94Q, OPA1:p.S545R and OPA1:p.R733X, show altered organization of the mitochondrial networks. (A) Representative images of controls and fibroblasts with OPA1:p.S545R and MFN2:p.R94Q mutations. Individual mitochondrial tubules are shown distinctively coloured. (B) Histograms indicate the number of individual mitochondrial tubules per total mitochondrial length; (C) the number of network branch points per total mitochondrial length; (D) the mitochondrial volume per cellular volume (convex hull algorithm); (E) and the bar diagram shows the distribution of mitochondrial lengths. Values of mutated skin fibroblasts are the mean ± s.d. of at least 40 measurements from two independent acquisitions. Control values are the mean ± s.d. of at least 160 measurements (X, XL or XXL cell size) from four healthy control cell lines. *P < 0.01, **P < 0.001, Mann–Whitney U-test. Scale bar: 10 μm.Dominant OPA1 mutations are associated with fragmented mitochondrial networks in fibroblasts from ADOA patients (Amati-Bonneau et al., 2005), and in HeLa cells transfected with OPA1 mutants (Olichon et al., 2007) but no reduction of mitochondrial volume has been described. In our study, the OPA1:p.S545R and OPA1:p.R733X mutations were associated with a higher ratio of individual mitochondrial tubules to total mitochondrial length (Fig. 3B). Unconnected mitochondria consisted of small tubular structures (Fig. 3E) with few dichotomous branches and a small number of connection points (Fig. 3C). Significantly, mitochondrial fragmentation in the OPA1:p.S545R cells was associated with a 20.5% reduction of mitochondrial volume compared to controls (P < 0.001; Mann–Whitney U-test) (Fig. 3D). The mitochondrial fragmentation observed in OPA1:p.R733X cells did not affect the total mitochondrial volume since the length of each individual tubule in these cells is longer than in OPA1:p.S545R cells.This fragmentation was associated with a disorganization of the mitochondrial network that did not affect cell size or shape. Interestingly, in OPA1:p.S545R cells, most mitochondrial tubular structures were found close to the MTOC (Fig. 3, Fig. 4) whereas isolated mitochondria were mainly found in the three extension arms of the triangular cell and around the nucleus. It would have been interesting to perform a statistical analysis of the variation of mitochondrial volume according to the various cell regions but the precise definition of these subregions for automatic anaylsis presented considerable difficulties. However, our visual analysis indicated that each region of the cell – central, perinuclear, and periplasmic – was equally affected by the reduction of mitochondrial volume in OPA1:p.S545R cells.Download : Download high-res image (848KB)Download : Download full-size imageFig. 4. Mitochondrial network of OPA1:p.S545R fibroblasts. (A) Mitochondrial network (in black) in control fibroblast (MitoTracker Green staining). (B) Mitochondrial network fragmentation induced by CCCP 10 μM 24 h. (C1–4) In OPA1:p.S545R fibroblasts, the major portion of the mitochondrial network was fragmented except for mitochondria emerging from the MTOC (white spots are supposed to indicate the position the MTOC). Representative images of at least 160 cells (X, XL or XXL cell size) from three control cell lines, acquired in two independent times. Scale bars: 10 μm.We noted that no tubular structures were preserved when mitochondrial fragmentation was induced by the mitochondrial uncoupler CCCP (Fig. 4B) or by siRNA OPA1 (supplementary material Fig. S4B).The expression of the GTPase-domain mutant of MFN2 (MFN2:p.K109T) in HeLa cells was shown to induce mitochondrial fragmentation (Detmer and Chan, 2007). However, standard fluorescent imaging revealed no mitochondrial network defects in heterozygous MFN2 CMT2A fibroblasts (Loiseau et al., 2007, Amiott et al., 2008). In contrast, our standardized technique of mitochondrial imaging showed that the missense mutation MFN2:p.R94Q induced mitochondrial biogenesis and the over-fusion of mitochondria. Reticulated mitochondria were distributed all over the cell (Fig. 3A) with a 24% higher number of mitochondrial network branch points compared to controls (P < 0.01; Mann–Whitney U-test) (Fig. 3C) and a 14.8% increase of mitochondrial content per cell compared to controls (P < 0.01; Mann–Whitney U-test) (Fig. 3D).In contrast to the mitochondrial fragmentation observed after neuroblastoma cell lines were transfected with GDAP1 mutants (Niemann et al., 2009), no alterations in mitochondrial network morphology were found in fibroblasts with the GDAP1:p.R120W mutation (Fig. 3).
Cultured fibroblasts from patients show that this variant results in altered organization of the mitochondrial network including a 20.5% reduction in mitochondrial volume compared to controls, a higher ratio of individual mitochondrial tubules to total mitochondrial length, unconnected mitochondria that consisted of small tubular structures (Fig. 3E) with few dichotomous branches and a small number of connection points, and fragmentation of the mitochondrial network (Fig. 4).
The index patient (V-1)
CaseV-1: Male, 27 yrs onset, China, Asian
CasePresentingHPOs: HP:0002875, HP:0001639, HP:0002027, HP:0001712, HP:0001671, HP:0032092, HP:0001645 (Exertional dyspnea, Hypertrophic cardiomyopathy, Abdominal pain, Left ventricular hypertrophy, Abnormal cardiac septum morphology, Left ventricular outflow tract obstruction, Sudden cardiac death)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Family is consanguineous, The MYPBC3 variant was the only one to segregate with the disease, with the CACNB2 variant also being present in individuals with "severe" forms of the disease. CACNB2+ MYH7- individuals showed no symptoms of cardiomyopathy, supporting a modifying effect leading to the clinical heterogeneity of this family, MYBPC3 variant leads to a premature termination and a loss of 49 amino acids which is predicted to undergo NMD but is also associated with incomplete penetrance
CasePreviousTesting: Marked hypertrophic septum (27 mm) and a left-ventricular outflow obstruction (LVOTO) of 32 mmHg, Clinical features in Table 1, No members showed Brugada syndrome phenotypes, Proband also has polymorphisms in TGFB1 and AKAP9 but no other affected family member contains them suggesting a benign pathogenicity
CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. PCR amplification was performed and sanger sequencing was performed for MYH7 and MYPBC3 mutations. After positive confirmation of the MYBPC3 mutation, RAAS genes were genotyped for a possible modifying effect. Negative findings led to a targeted NGS for the index patient using all known 104 causing/closely related genes of cardiomyopathy and chanelopathy. These variants were then filtered and analyzed for pathogenicity and confirmed in family members via Sanger sequencing.
Variant: NM_201597.3:c.1598C>T (p.Ser533Leu)
ClinVar: 190730 https://www.ncbi.nlm.nih.gov/clinvar/variation/190730/
gnomAD: 0.01004, https://gnomad.broadinstitute.org/variant/10-18828340-C-T
MultipleGeneVariants
MYBPC3 Variant
Variant: NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs)
ClinVar: 42727 https://www.ncbi.nlm.nih.gov/clinvar/variation/42727/
gnomAD: 0.00005140, https://gnomad.broadinstitute.org/variant/11-47354119-TG-T
DSP Variant
Variant: NM_004415.4(DSP):c.3923G>A (p.Arg1308Gln)
ClinVar: 178028 https://www.ncbi.nlm.nih.gov/clinvar/variation/178028/
gnomAD: 0.01680, https://gnomad.broadinstitute.org/variant/6-7580346-G-A
Molecular analysis of the PAX6 gene in Mexican patients with congenital aniridia: report of four novel mutations
PMID: 18776953
Gene: PAX6
Variant c.-129+9G>A
Disease: Ocular dysgenesis
MonDO: MONDO:0700246
InheritancePattern: AD
For each patient, the summary of clinical and molecular data is tabulated in Supplementary Table 3. The synonymous variants identified for each patient are given in Supplementary Table 4.
Proband - Case 21
Male, Dx at 22 yrs, MWT=30mm, LVM=148mg/m2, LVEF=75%
HP:0001639, HCM
Varient: NM_145046.4(CALR3):c.1036A>G (p.I346V)
Not in Clinvar
ExAC Score: Overall 1.647e-05
Family 5/Case 1/M/43 + +/+ + +/+ Diffuse myalgia + RRFs/COX - + NA c.1635 C > G (p.S545R)
Case#: Family 5 Case 1, male, 43yo, south France
DiseaseAssertion: OA plus
FamilyInfo: mother and brother also had optic atrophy, but further details such as genotype and more phenotype information were not confirmed
CasePresentingHPOs: HP:0000648, HP:0000508, HP:0000365, HP:0001251, HP:0002403, HP:0003326, HP:0009830, HP:0003200, HP:0000590, HP:0003688, HP:0003390,
CaseHPOFreeText: visual impairment since childhood, colic occlusion without any evident mechanical cause, impaired sensation to all modalities predominantly in the lower limbs, atrophy of the corpus callosum and brainstem and a mild cerebellar atrophy, bilateral basal ganglia hypointensity was detected at T2-weighted MRI scan
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished:
PreviousTesting: Direct sequencing of the complete coding region and the exon/intron boundaries of the genes POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1). mtDNA multiple deletions present.
GenotypingMethod: genomic DNA was amplified by PCR with specific primers designed to amplify all exons and flanking intronic regions and sequenced. Southern blot analysis, long-range PCR, sequencing in both directions, and quantitation of mtDNA relative to nuclear DNA was performed on mtDNA
Variant: c.1635 C > G (p.S545R)
ClinVar: 30461
CAID: CA10575554
SupplementalData:
o determine the frequency of MYOZ2 mutation in HCM, we screened all exons and exon–intron boundaries of MYOZ2 in 516 probands by direct sequencing. We detected another heterozygous missense A→G mutation at nucleotide 50 278 in a white proband who had 2 deceased siblings with HCM. The mutation changed amino acid isoleucine 246, a conserved amino acid, to methionine
Case 2: male, Dx = n/a, variant identified via direct sequencing
HP:0001712 (left ventricular hypertrophy)
Variant: NM_016599.4(MYOZ2):c.738A>G (p.Ile246Met)
non-LOF
ClinVar ID: 30509, conflicting interpretations of pathogenicity,<br /> https://www.ncbi.nlm.nih.gov/clinvar/variation/30509/
ExAC Score: 0.001897, http://gnomad.broadinstitute.org/variant/4-120107298-A-G
The index case presented at 12 years of age with symptoms of diastolic heart failure and episodes of syncope (supplemental Table I available in the online data supplement available at http://circres.ahajournals.org.). She had severe left ventricular hypertrophy with a septal thickness of 3.2 cm, atrial fibrillation, and runs of ventricular tachycardia.
Case: Family 109, female, Dx = 12 yrs, septal thickness 3.2cm
Family had 6 affected individuals sharing MYOZ2 haplotype 4q26-q27
HP:0001635, HP:0001279, HP:0001712, HP:0005110, HP:0004755
heart failure, syncope, left ventricular hypertrophy, atrial fibrillation, supraventricular tachycardia
Variant: NM_016599.4(MYOZ2):c.142T>C (p.Ser48Pro)
Pathogenic, non-LOF
ClinVar ID: 30508 https://www.ncbi.nlm.nih.gov/clinvar/variation/30508/
Not in ExAC or gnomAD
Dutch patient
Case1: Female, 12 yrs onset, Dutch
CasePresentingHPOs: HP:0002093, HP:0001288, HP:0003690, HP:0010628, HP:0003722, HP:0003202, HP:0003798 (Respiratory insufficiency, Gait difficulties, Limb muscle weakness, Facial muscle weakness, Neck flexor weakness, Muscle hypotrophy, Nemaline rods)
HPOsFreeText: Mild form of nemaline myopathy, Wheelchair from the age of 48, Selective hypotrophy of Type 1 muscle fibres
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: No family history of neuromuscular disorders, Variant was not detected in healthy mother or 7 unaffected siblings, Father was deceased so no sample was available
CasePreviousTesting: N/A
CaseGenotypingMethod: Genomic DNA and RNA was extracted from blood or lymphoblastoid cell lines. SSCP was used to analyze all 10 exons of TPM2. After locating the mutations, RT-PCR was used to confirm the mutated allele expression and haplotype analysis was performed on the probands and their family.
Variant: NM_003289.3:c.440A>C (p.Gln147Pro)
ClinVar: 12461 https://www.ncbi.nlm.nih.gov/clinvar/variation/12461/
gnomAD: Not in gnomAD
Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism
PMID 30098700
PMID: 9536098
Gene: PAX6
Variant NM_001368894.2:c.-128-2del
Disease: Ocular dysgenesis
InheritancePattern: AD
Disease PAX6-related ocular dysgenesis MONDO:0800183
two unrelated patients
CaseRoma: France
CasePresentingHPOs: HP:0006785, HP:0003236, (Limb-girdle muscular dystrophy, Elevated serum creatine kinase)
HPOsFreeText: Wheelchair bound before 14 yrs
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Probands are from consanguineous gypsy families supporting a founder event, This mutation segregated with the disease in 18 patients and all asymptomatic parents were heterozygous, 15 siblings were heterozygous and asymptomatic except for a moderate increase in Serum CK in some
CasePreviousTesting: Duchenne-like clinical presentation, Males and females equally affected, Normal dystrophin and decreased level of α- and γ-SG in muscle specimens
CaseGenotypingMethod: DNA was isolated from peripheral blood leukocytes and subject to PCR amplification for linkage analysis. Total RNA was extracted from muscle biopsies and cDNA synthesis was performed and amplified. This was sequenced and analyzed for mutations.
Variant: NM_000231.2(SGCG):c.848G>A (p.Cys283Tyr)
ClinVar: 2006 https://www.ncbi.nlm.nih.gov/clinvar/variation/2006/
gnomAD: 0.000008796, https://gnomad.broadinstitute.org/variant/13-23898652-G-A
Affected: 18
Unaffected: At least 29
Segregations: N/A
SegregationAddInfo: Candidate Gene Sequencing
the Arg73Gln (exon 3) mutation was identified in the proband (II:1), a 28-year-old male who had been diagnosed with FHC at age 18 years and on echocardiography was found to have severe asymmetric septal hypertrophy. He has a family history of FHC, but other family members have not been willing to participate in further evaluation. Previous genetic screening of sarcomere genes identified two missense mutations in myosin-binding protein C (MyBPC3; Asp745Gly and Pro873His)
Proband 1: male, Dx at 18 years, LV septal wall thickness = 30mm, family history of HCM with father and brother affected
HP:0001639, HP:0001670
Hypertrophic cardiomyopathy, asymmetric septal hypertrophy
Variant: NM_145046.4(CALR3):c.218G>A (p.Arg73Gln).
Not in ClinVar
ExAC Score: Overall 1.624e-5
Patient 2
Case2: Female, Birth onset, Germany
CasePresentingHPOs: HP:0003552, HP:0001558, HP:0002375, HP:0002747, HP:0004887, HP:0001385, HP:0001537, HP:0000023, HP:0012418, HP:0000278, HP:0000347, HP:0000470, HP:0001276, HP:0002808, HP:0001376, HP:0002063, HP:0011968, HP:0000975, HP:0003236, HP:0000938, HP:0009803, HP:0030084, HP:0001561, HP:0002828, HP:0005949, HP:0001284, HP:0003198, HP:0003557, HP:0003687, HP:0010602 (Muscle stiffness, Decreased fetal movement, Hypokinesia, Respiratory insufficiency due to muscle weakness, Respiratory failure requiring assisted ventilation, Hip dysplasia, Umbilical hernia, Inguinal hernia, Hypoxemia, Retrognathia, Micrognathia, Short neck, Hypertonia, Kyphosis, Limited joint motion, Rigidity, Feeding difficulties, Profuse sweating, Elevated serum creatine phosphokinase, Osteopenia, Shortened phalanges, Clinodactyly, Polyhydramnios, Multiple joint contractures, Apneic episodes in infancy, Areflexia, Myopathic changes, Increased variability in muscle fiber diameter, Centrally nucleated skeletal muscle fibers, Type 2 muscle fiber predominance)
HPOsFreeText: Tracheostomy performed, Bladder catheter required, Inability to sit or roll, Increased echogenicity on muscle ultrasound, Treatment with carbamazepine, benzodiazepines, and baclofen reportedly provided no substantial benefit, Difficulty sitting due to hyperactivity of hip extensors, Mini rods and z-band broadening were seen in atrophic fibers
CaseNotHPOs: HP:0100543, HP:0003730, HP:0002486, HP:0002353, HP:0002363, HP:0000496, HP:0003202, HP:0003798 (Cognitive impairment, EMG: myotonic runs, Myotonia, EEG abnormality, Abnormality of brainstem morphology, Abnormality of eye movement, Skeletal muscle atrophy, Nemaline bodies)
NotHPOsFreeText: Abnormal metabolic screening, Muscle fiber type grouping
CaseAddInfo: Case is de novo and confirmed via parental testing
CasePreviousTesting: Negative ACTA1 and CRYAB
CaseGenotypingMethod: Based on the Patient 1 results, the same region of TPM3 (Exon 6) was PCR amplified and sequenced in the proband and her parents via bidirectional Sanger sequencing.
Variant: NM_152263.4(TPM3):c.654_656AGA[1] (p.Glu219del)
ClinVar: 235144 https://www.ncbi.nlm.nih.gov/clinvar/variation/235144/
gnomAD: Not in gnomAD
OA-16c.1635C>Gp.S545R333.71.0-5.020/117020/200 - HM
Case#: Pedigree OA-16, North of England
DiseaseAssertion: optic atrophy
FamilyInfo: 2 additional affected individuals
CasePresentingHPOs: HP:0000648
CaseHPOFreeText: Snellen BCVA 20/200 - hand movement, mean age of onset= 3.7yrs
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: Cautious that they may overlap with the individuals from Hudson et al since both are from England, but the author notes that they "checked against the eOPA1 database (http://lbbma.univ-angers.fr/eOPA1/, Accessed 10-12-09) to determine whether they had been described in previous mutational reports."
GenotypingMethod: The entire coding region of the OPA1 and OPA3 genes was amplified by PCR and sequenced. Variants were confirmed by reverse sequencing.
Variant: c.1635C>G; p.S545R
ClinVar: 30461
CAID: CA10575554
SupplementalData:
The proband
Case#: two affected sisters
DiseaseAssertion: Stargardt Disease
FamilyInfo: compound heterozygotes for the mutations. Unaffected family members did not carry either or had one of the two mutations.
CasePresentingHPOs: NR
CaseHPOFreeText: NR
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: ABCA4 408 microsatellite
PreviouslyPublished: NR
Variant: NM_000350.3(ABCA4):c.5018+2T>C , NM_000350.3(ABCA4):c.655A>T
ClinVar: 265008, 632118
CAID: CA10588304, CA645372240
SupplementalData: NR
Current age 26 years
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:L238Q
Variant1ClinVarID:265418
Variant1CAID:
Variant2:W402X
Variant2ClinVarID:
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:L238Q
Variant1ClinVarID:265418
Variant1CAID:
Variant2:63delC
Variant2ClinVarID:
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:65delC
Variant1ClinVarID:
Variant1CAID:
Variant2:H240R
Variant2ClinVarID:947028
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
identified a heterozygous c.121C > T, p.R41W missense mutation in CRX in all 3 affected members
ABCA4
Phenotype–genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion–insertion variant causing a splicing defect
PMID: 32627976
Gene: ABCA4
HGNC ID: 34
Disease: Von-willebrand Disease (Type 2A)
Patient: 50 yo female
Variant: VWF NM_000552.5 c:4232_4249del p.(Val411_Ile416del), Exon 28, heterozygous variant
According to this paper, ACMG-AMP guidelines for interpreting this variant resulted in classification of likely pathogenic
Phenotypes: increased bruising, fatigue, recurrent sinusitis, menorrhagia, neutropenia, anaemia. Reduction in high-molecular-weight multimers
Family: segregation analysis showed two affected family members had the variant and two unaffected family members did not have variant.
Note: Patient also has diagnosed Acute Myeloid Leukaemia (AML) NM_000546.6(TP53):c704A>G p.(Asn235Ser), listed as VUS and found by NGS
Disease: Von-willebrand Disorder (2N)
Patient: 32 yo, male
Variant: VWF NM_000552.5 c:2527C>T, p.(Arg760Cys), exon 17, noted to be dominant effect
Note: Proband also has an Arg91Gln mutation in exon 20 of VWF too.
Phenotypes: Mild bleeding history, epistaxis, bleeding gums, bleeding after tooth extraction. 11 years old had severe hemorrhage following tonsillectomy. Previous diagnosis of hemophilia A.
Family: father has history of epistaxis but never eamined prior to study. Father has the Arg760Cys mutation at heterozygous level. Mother is asymptomatic and classified as hemophilia A carrier following hemophilia A diagnosis in son. Mother also has the Arg91Gln mutation in exon 20 at heterozygous level.
Molecular Phenotypes: mild decrease in plasma FVIII and VWF levels, normal platelet VWF content, decreased FVIII binding capacity of VWF. Causes retention of pro-VWF(suggest defects in the maturation process of VWF). Abnormal VWF and platelet GPIb interaction(documented by impaired or absent RIPA and decreased VWF:RCo).
Disease: Von-willebrand Disorder Type 2B, Noncanonical
Patient: 55 YO, Italian male
Note: these heterozygous variants are in cis mutations
Variant1: VWF NM_000552.5 c.2771G>A p.(R924Q), in exon 21, D'D3 domain affected
Variant2: VWF NM_000552.5 c.6532G>T p.(A2178S), in exon 37, D4 domain affected
Phenotypes: Mucosal and cutaneous bleeding, low VWF antigent and VWF activity, mild thrombocytopenia, increased ristocetin-induced platelet aggregation, deficiency in high-molecular-weight multimers. Epistaxis, repeated GI bleeding, easy bruising, ISTH BAT score of 7.
Note: Proband initially diagnosed with VWD type 1 in 2010 but later re-diagnosed as VWD-Type 2.
Family: No reported family history of bleeding, parents unable to be included in family work-up as they were deceased by time of study. Paternity test was performed for family, parental link established. Patient's daughter does not present the same mutation noted in proband but has heterozygous polymorphic variant inherited from mother which is: VWF NM_000552.5 c.3379C>T p.(P1127S), in exon 25. Daughter did not show menorrhagia or hemorrhagic disorder except for large hematoma on the thigh after trauma of moderate intensity.
Molecular workup: Paternity test, Sanger-sequencing to validate genetic variants, multimer analysis with electrophoresis, platelet aggregation analysis with Ristocetin, electron micrographs to observe conformation differences.
Prediction workup: Structural analysis with I-TASSER modeling program to identify perturbed structure. A2178S is predicted as tolerated in all in-silico systems used.
Database Information: Effect of the R924Q mutation is noted in literature database but has contradicting reports of effects altering VWF levels. Some studies do report it as a polymorphic variant
Variant is present in dbSNP database (rs33978901). MAF in European population 0.01< MAF< 0.02
Effect of A2178S variant is present in dbSNP database (rs34230288), MAF = 0.02 in European population.
Disease: Myopathic Ehlers-Danlos Syndrome (mEDS)
Patient(s): 47 yo male, japanese descent
Variant: COL12A1 NM_004370.6: c.395-1G>A (Homozygous variant, at splice acceptor site in exon 6, causes in-frame skipping)(located in the genomic region encoding the first von Willebrand factor A domain)
Family: consanguineous parents with no related features of mEDS, healthy older brother
Phenotypes (Childhood): hypotonia, weak spontaneous movements, scoliosis, torticollis, soft plams, undescended testes, motor developmental delay, slender build, triangular face, short palpebral fissures, small nose, small mouth, large ears, bilateral knee dislocations, short stature.
Phenotypes (Adulthood): short stature, high palate, hypermobile small joints, deformed cervical spine, brachycephaly, bilateral long deformed 5th finger, severe scoliosis post surgical fixation, asymmetric pelvis
Classification: sequencing panel found the variant and it was confirmed through sanger sequencing.
According to ClinGenSVI recommendation: PVS1_Strong
Applicable criteria:
1) the one at a GT-AG 1,2 splice site
2) the one exerting exon skipping or use of a crypic splice site that preserved the reading frame.
3) the one at a truncated/altered region critical to protein function; was classified as PM3_Supporting (homozygous)
Variant not registered in gnomAD (PM2_Supporting)
Partial defect of first vWA in collagen XII judged as PS3
Disease: Von Willebrand Disease (VWD)
Patient(s): Found in 2 families
Variant: VWF NM_000552.5: c.2311A>G, p.(M771V Homozygous variant in exon 18 (VWF D' domain; 8 residues down from proteolytic VWFpp furin cleavage site)
Family: In family 1 there are 4 homozygous patients (2 male and 2 female), and one heterozygous patient (1 female). The affected females are denoted as person 1 and person 4 and the affected males are person 2 and person 3. There are three WT family members (1 female and 2 male), grandparents of these members are of unknown genotype including a daughter of an affected female and a WT male. Note here that in the family a p.R2663P variant has co-segregated with the above-mentioned variant but is not suspected to be the pathogenic driver of resulting bleeding tendency.
In family 2 the parents of the homozygous affected male are of unknown genotype. The affected male is denoted as person 7.
Phenotypes: Person 1- nose bleed, skin bleed, GI bleeding, oral cavity bleeds, Menorrhagia, muscle bleeding, and joint bleeding. Receives on-demand treatment for bleeding.
Person 2-Nose bleed, skin bleed, bleeding from small wounds, oral cavity bleeds, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment, reduced to on-demand treatment after a few years.
Person 3-Nose bleed, skin bleed, oral cavity bleeds, bleeding after tooth extraction, muscle bleeding. Receives on-demand treatment for bleeding phenotype.
Person 4- Nose bleed, bleeding from small wounds, oral cavity bleed, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment that was increased after her menarche.
Person 7- Nose bleed, oral cavity bleeds, bleeding after surgery or trauma, joint bleeding. Previously on prophylaxis, now managing bleeding with on-demand treatment.
Note that both the p.R2663P co-segregated variant and p.M771V variant are reported in NCBI dbSNP database but functional effect not yet established.
NGS confirmed the genotype of all study participants.
Disease: Von-willebrand Disorder Type 3
Patient: 26 yo, female
Variant: VWF NM_000552.5 c:997+118 T>G g.(6073501 A>C), homozygous, intronic
Phenotypes: No detectable VWF in plasma, early onset bleeding complications, epistaxis, easy bruising, bleeding following injury, menorrhagia, iron-deficient anemia
Note: underwent prophylaxis replacement therapy, on-demand antihemorrhagic treatments, oral contraceptives, and replacement therapy.
Family: not mentioned
Predictions:
VEP SpliceAI tool predicted variant likely deleterious (delta score 0.95)
Used Polyphen-2 and SIFT which determined pathogenic likelihood.
Neural Network Splicing, Alternative Splice Site Predictor, plug-in MaxEnt(For 5' donor site) of Human Splicing Finder all concur this variant can create a new donor splice site in intron 8. Contains premature stop codon and susceptible to NMD.
Functional work:
qRT-PCR performed to identify levels of VWF in IP-derived endothelial cells.
histochemical immunostaining for IP-derived endothelial cells confirm no VWF production, only a residual amount present. Suggests leaky mutation.
performed RNA sequencing to assess co-regulated gene networks
Disease: Platelet-type Von-willebrand Disorder (PT-VWD)
Patient: 17 yo, male, adopted
Variant: GP1BA NM_000173.7: c:580C>T p.(P.Leu194Phe), Heterozygous, gain-of-function
Phenotypes: moderate bleeding phenotype, ISTH-BAT bleeding score of 3, recurrent epistaxis, easy bruising, mild thrombocytopenia
Family: Adopted, no other family history mentioned, segregation studies not performed.
Genetic analysis performed: found variant in GP1BA, results obtained by sanger sequencing.
Variant present in gnomAD(rs368111193): low allele frequency, contradictory classifications
Variant is not present in ClinVar, LOVD, or HGMD databases
According to this paper, ACMG guidelines classified this variant as a VUS.
This paper entered it into Clinvar (var ID 1693270)
Disease: Von Willebrand Disease (VWD) Type 2A
Patient: 31 yo, Female
Variant1: VWF NC_000012.12: c.875-5T>Gdel, p.(Ser292_Glu333delinsLys) Causes complete exon 8 skipping
Variant2: VWF NM_000552.5: c.813C>G, p.(Tyr271*)
Phenotypes: History of bleeding (epistaxis, uncontrollable by conventional hemostatic treatment), Easy bruising, gum bleeding, excessive menstrual bleeding, mild decrease in plasma VWF:Ag, severe impairment in VWF function, VWF:Ab/VWF:Ag ratio decreased, VWF:CB/VWF:Ag ratio decreased, FVIII:C lvs slighly below normal range
Family: Son had bleeding diathesis and spontaneous epistaxis (less severe than proband), normal parents
In silico data available: SpliceAI delta score of 0.51 for loss of splice acceptor caused by variant 1
Alamut showed small to moderate effects of the variant on normal splicing of VWF
NetGene2 showed weak strength of 3' splice sites in exon 8
SpliceAid2 showed TIA-1 and TIAL 1, which bind to U-rich motifs and facilitate 5' splice site recognition where destroyed in the mutated sequence
Disease: Von-Willebrand Disorder
Patient 2 Variant(s):
VWF NM_000552.5: c.4135C>T p.(Arg1379Cys) Exon 28 VWF NM_000552.5: c.4130C>T p.(Ala1377Val) Exon 28 VWF NM_000552.5: c.3797C>T p.(Pro1266Leu) Exon 28 VWF NM_000552.5: c.3835G>A p.(Val1279Ile) Exon 28
Note: Pro1266Leu and Val1279Ile are in trans with Ala1377Val and Arg1379Cys
Note2: MAF of Ala1377Val is present in Exome Variant Server (<0.01) and 1000 Genomes database (<0.02), designated as rare variant, typically found in indiv with African ethnicity
Family: Relatives molecular analysis showed Arg1379 and Ala1377Val variants mentioned above were in cis
Patient 2 Phenotype: Mild bleeding symptom Nearly normal VWF:Ag value, reduced VWF:RCo value slight loss of HMWM with smear decreased/slightly decreased proteolysis Slightly reduced RIPA VWFpp/VWF:Ag ratio shows increased VWF clearance VWF platelet levels reduced reduced rBpIba binding in VWF plasma VWF:GPIbM values slightly increased
Note: Treated with desmopressin in case of minor surgeries or delivery
Note 2: Slightly decreased RIPA may be explained by presence of 2B New York Variant (Pro1266Leu) that mitigates RIPA assay in 2M phenotype.
In silico analysis available:
I-Mutant 3.0 states decrease in A1 domain stability for both mutations (Ala1377Val = -0.91, Arg1379Cys = -1.36)
PYMOL predicts Ala1377Val does not alter formation of hydrogen bonds with Arg1374 residue and water. Predicts substitution of ARG 1379 with a cysteine results in the loss of hydrogen bonds with Lys1407 and Lys1408, predicted change in secondary structure of A1 domain
Ala1377Val was previously reported in 3 other patients Publications:
Millar CM, Riddel AF, Mellors G, Yee TT. The spectrum of VWD type 2 phenotypes associated with A1 domain mutations posters. J Thromb Haemost 2009; 7: 531–2.
Logsdon BA, Dai JY, Auer PL et al. A variational Bayes discrete mixture test for rare variant association. Genet Epidemiol 2014; 38: 21–30.
Final note: Authors suggest patients' 2M phenotype is due to the presence of Ala1377Val and Arg1379Cys together to create synergistic effect. Though difficult to discern with this specific patient having two other variants in addition to the two mentioned above.
In at least one other published version the first two items on this list are not peacock fans and Japanese screens but “ormolu garden gates, handleless cups”. The Oxford Book of Victorian Ghost Stories, ed. Michael Cox and R.A. Gilbert
Ormolu is the gilding technique of applying finely ground, high-carat gold–mercury amalgam to an object of bronze, and for objects finished in this way. The mercury is driven off in a kiln leaving behind a gold coating. The French refer to this technique as "bronze doré"; in English, it is known as "gilt bronze". https://en.wikipedia.org/wiki/Ormolu?wprov=sfti1
peacock fans, Japanese screens,
In at least one other published version the first two items on this list are not peacock fans and Japanese screens but “ormolu garden gates, handleless cups”. The Oxford Book of Victorian Ghost Stories, ed. Michael Cox and R.A. Gilbert
Ormolu is the gilding technique of applying finely ground, high-carat gold–mercury amalgam to an object of bronze, and for objects finished in this way. The mercury is driven off in a kiln leaving behind a gold coating. The French refer to this technique as "bronze doré"; in English, it is known as "gilt bronze". https://en.wikipedia.org/wiki/Ormolu?wprov=sfti1
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Sandra Ciesek. (2021, December 8). Unsere ersten Daten zur Neutralisation von Omicron versus Delta sind fertig: 2x Biontech, 2x Moderna, 1xAZ/1x Biontech nach 6 Monaten 0% Neutralisation bei Omicron, auch 3x Biontech 3 Monate nach Booster nur 25% NT versus 95% bei Delta. Bis zu 37fache Reduktion Delta vs. Omicron https://t.co/w0gHww26sg [Tweet]. @CiesekSandra. https://twitter.com/CiesekSandra/status/1468465347519041539
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ReconfigBehSci. (2021, December 14). RT @thehowie: "...The vaccine provided 70 percent protection in fully vaccinated individuals against severe complications that would requir… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470749072160133128
How are new Covid cases impacting sport? (n.d.). BBC Sport. Retrieved December 23, 2021, from https://www.bbc.com/sport/59682938
ReconfigBehSci. (2021, December 14). RT @thehowie: BREAKING South Africa: 82% increase in cases, week over week. 34.9% positive rate. Record 7-day average. Not near platea… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470814593610047490
Dr Nisreen Alwan 🌻. (2021, December 23). We’re in unchartered territory. Https://t.co/O1GGcXpMll [Tweet]. @Dr2NisreenAlwan. https://twitter.com/Dr2NisreenAlwan/status/1474051397570248716
Kai Kupferschmidt. (2021, December 10). “the severity profile of Omicron cases must be interpreted along with an understanding of its capacity to re-infect (and infect the vaccinated)“ This is what I have been trying to explain the last few days. As usual @nataliexdean does it better (and in color)! [Tweet]. @kakape. https://twitter.com/kakape/status/1469270407995867139
Yaniv Erlich. (2021, December 8). Updated table of Omicron neuts studies with @Pfizer results (which did the worst job in terms of reporting raw data). Strong discrepancy between studies with live vs pseudo. Https://t.co/InQuWMAm4l [Tweet]. @erlichya. https://twitter.com/erlichya/status/1468580675007795204
ReconfigBehSci. (2021, December 12). RT @ryan_landay: > A new diverse genome has appeared within the B.1.1.529 lineage that has all of the shared mutations of B.1.1.529, some o… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470066521615605766
ReconfigBehSci. (2021, December 9). RT @RachelLavin: As Omicron reality dawns, consider investing in better masks: "....Tight-fitting FFP2 masks provide 75 times better pro… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1474030898551087113
Campbell, D., Sabbagh, D., & Devlin, H. (2022, January 7). Military deployed at London hospitals due to Omicron staff shortages. The Guardian. https://www.theguardian.com/world/2022/jan/07/military-deployed-at-london-hospitals-due-to-omicron-staff-shortages
ReconfigBehSci. (2021, November 26). RT @mvankerkhove: Following the meeting of the @WHO TAG-VE today, WHO classifies B.1.1.529 as a variant of concern named Omicron. We call… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464302372100976650
ReconfigBehSci. (2021, December 12). RT @EricTopol: If you think Prior Covid protects against Omicron (B.1.1.529), think again https://medrxiv.org/content/10.1101/2021.12.08.21267491v1 and "Neutralizing antibo… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470434736304803845
ReconfigBehSci. (2021, November 26). vaccine equity has been a disaster, but I do wonder whether the exclusive focus on donations does the US/EU comparison justice. The EU allowed the export of huge numbers of EU produced doses at a time when the US did not (and EU itself was struggling to meet demand). [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464255575416520749
ReconfigBehSci on Twitter: “RT @BNODesk: BREAKING: U.S. reports 716,714 new coronavirus cases, setting world record for cases in one day” / Twitter. (n.d.). Retrieved January 7, 2022, from https://twitter.com/SciBeh/status/1478987541332348933
Karan, A. (2022). We cannot afford to repeat these four pandemic mistakes. BMJ, 376, o631. https://doi.org/10.1136/bmj.o631
ReconfigBehSci. (2021, December 23). Risk of hospital stay 40% lower with Omicron than Delta, UK data suggests https://t.co/VupN8hY4qq [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473916654421643266
ReconfigBehSci. (2021, November 26). maybe this is a good moment to remind people that makers of mRNA vaccines have been extensively prepping for the possibility of new variants. Biontech/Pfizer have given a timeline of 100 days to the delivery of a retooled version of their vaccine [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464225264523747359
Eric Topol. (2022, January 2). As the world turns.....vertical the Omicron signature (|) @OurWorldInData https://t.co/LOBiaiBapD [Tweet]. @EricTopol. https://twitter.com/EricTopol/status/1477433315896430592
Kissane, E. (2021, December 23). We’re About to Lose Track of the Pandemic. The Atlantic. https://www.theatlantic.com/ideas/archive/2021/12/were-about-to-lose-track-of-the-pandemic/621097/
ReconfigBehSci. (2021, December 11). RT @MackayIM: Booster access brought forward to slow spread of Omicron COVID-19 variant https://t.co/PukbPydylw [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469633384511119364
ReconfigBehSci. (2021, December 13). RT @DrEricDing: 11) Omicron is doubling every 1.6 days in UK 🇬🇧 according to @DrWilliamKu’s figure. That’s way faster growth than in South… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470451594378502154
Prof. Christina Pagel. (2021, December 23). UKHSA surveillance report shows reinfections rising sharply as Omicron takes hold https://t.co/UGArY4sbOA [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1474041921249189896
ReconfigBehSci. (2021, December 13). Important update on the now withdrawn @BallouxFrancois tweet identifying hopeful turning of the corner in SA omicron data [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470311016114364420
Thomas, T., & Duncan, P. (2021, December 23). If Omicron is the dominant variant in UK, why is the number of confirmed cases so low? The Guardian. https://www.theguardian.com/world/2021/dec/23/if-omicron-is-the-dominant-variant-in-uk-why-is-the-number-of-confirmed-cases-so-low
ReconfigBehSci. (2021, December 11). RT @DrEricDing: DOUBLING % in one day: The spike of probable #Omicron variant in Scotland🏴 has critically surged—Now at 13.3%, up fro… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469596523222781954
ReconfigBehSci. (2021, December 8). RT @kallmemeg: NEW: @UKHSA Mini Omicron Update Omicron VOC-21NOV-01 (B.1.1.529) update on cases, S gene target failure and risk assessment… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1468673329494216726
John Burn-Murdoch. (2021, November 25). Five quick tweets on the new variant B.1.1.529 Caveat first: Data here is very preliminary, so everything could change. Nonetheless, better safe than sorry. 1) Based on the data we have, this variant is out-competing others far faster than Beta and even Delta did 🚩🚩 https://t.co/R2Ac4e4N6s [Tweet]. @jburnmurdoch. https://twitter.com/jburnmurdoch/status/1463956686075580421
CNN, I. K. (n.d.). Vaccine inequity and hesitancy made the Omicron variant more likely, scientists say. CNN. Retrieved December 23, 2021, from https://www.cnn.com/2021/11/28/world/omicron-coronavirus-variant-vaccine-inequity-intl-cmd/index.html
ReconfigBehSci. (2021, December 22). RT @chrischirp: Positivity rising steeply too—There are definitely many more people we aren’t catching https://t.co/4xDPwYQtrx [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473695678610214927
ReconfigBehSci on Twitter: “RT @chrischirp: As well as Tom’s new one (B.1.1.529), C.1.2 seems to be spreading in S Africa—C.1.2 was the one with lots of worrying mut…” / Twitter. (n.d.). Retrieved December 23, 2021, from https://twitter.com/SciBeh/status/1463597407082532864
ReconfigBehSci. (2021, December 16). RT @MadsAlbertsen85: #Omicron update from Denmark. Omicron cases on the 12th of December adjusted up to 20.5% (+2%). Omicron is now having… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1471516083819462670
ReconfigBehSci. (2021, December 11). RT @thehowie: BREAKING: Hospitalizations South Africa Hospitalizations⬆️67% week over week. Gauteng Province⬆️66%. GP⬆️1.6% from yesterd… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469685234149072897
ReconfigBehSci. (2021, December 9). a rather worrying development- a (local) newspaper “fact checking” the new German health minister simply by interviewing a virologist who happens to have a different view. There’s simply no established “fact” as to the severity of omicron in children at this point in time [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469037817481334786
Trevor Bedford. (2021, December 11). We find that logistic growth of Omicron sequence fraction looks similar between the UK, the US and Germany with roughly 1% of sequenced cases in all three countries being Omicron on Dec 1. 3/10 https://t.co/De0t2xreU9 [Tweet]. @trvrb. https://twitter.com/trvrb/status/1469784757261127685
Gollub, R. L. (2022). Brain changes after COVID revealed by imaging. Nature. https://doi.org/10.1038/d41586-022-00503-x
ReconfigBehSci. (2021, December 17). RT @EricTopol: No evidence that Omicron is less severe, new @imperialcollege study reports https://ft.com/content/020534b3-5a54-4517-9fd1-167a5db50786 https://t.co/5YYzJ6tVtc [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1472156681098469380
ReconfigBehSci. (2021, November 26). RT @HZiauddeen: 🧵 COVID-19 & B.1.1.529: A chance for govt & others to change their mind and their approach? While we are still gathering d… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464200877888184324
ReconfigBehSci. (2021, December 22). RT @chrishendel: We need increased targeted measures now to slow the spread of #Omicron by @DrSarahHal via @bmj_latest https://t.co/3Tx… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473987200509521925
Perspective | Even the best-case scenario with omicron will still be bad. (n.d.). Washington Post. Retrieved December 23, 2021, from https://www.washingtonpost.com/outlook/2021/12/21/omicron-mild-cases-numbers/
Covid: Dutch go into Christmas lockdown over Omicron wave. (2021, December 18). BBC News. https://www.bbc.com/news/world-europe-59713503
Nature Portfolio. (2021, October 15). A study in @NatureMedicine indicates that the effectiveness of the Pfizer/BioNTech and Oxford-AstraZeneca vaccines against SARS-CoV-2 infections with symptoms or high viral burden is reduced with the Delta variant compared to the Alpha variant. Https://go.nature.com/3vecpoj https://t.co/XQdnMYguFz [Tweet]. @NaturePortfolio. https://twitter.com/NaturePortfolio/status/1449145321188216836
Prof. Shane Crotty. (2021, October 19). 1/ The regular vaccines give great booster responses against Delta and other variants This was first shown by Moderna, with “original recipe” vaccine booster, compare to Beta booster. Https://nature.com/articles/s41591-021-01527-y https://t.co/g7YDwGIURP [Tweet]. @profshanecrotty. https://twitter.com/profshanecrotty/status/1450489709050744833
ReconfigBehSci [@SciBeh]. (2021, November 26). RT @mvankerkhove: I thank researchers from 🇿🇦 and 🇧🇼 for sharing information with @WHO & the world about B.1.1.529 variant that has been re… [Tweet]. Twitter. https://twitter.com/SciBeh/status/1464196599773642779
ReconfigBehSci. (2021, December 20). RT @thehowie: South Africa Deaths (7 day average) are near double levels of a few weeks ago. They will go up further. They are only 7.5%… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1472991477672419334
Yale researchers develop RNA-based therapy that clears SARS-CoV-2 from mice. (n.d.). EurekAlert! Retrieved January 9, 2022, from https://www.eurekalert.org/news-releases/934454
whole-genome sequencing (WGS) provides the highest possible subtyping resolution improving the surveillance, outbreak investigation, source attribution, and microbial population studies
DICER1 syndrome is an autosomal-dominant, pleiotropic, tumor-predisposition disorder arising from pathogenic germline variants in DICER1, which encodes an endoribonuclease integral to processing microRNAs (1).
Gene Name: DICER1 PMCID: PMC5443331 PMID: 28323992 HGNCID: not found Inheritance Pattern: autosomal dominant Disease Entity: thyroid cancer and familial multinodular doiter Mutation: germline loss-of-function mutation Zygosity: not provided Variant: c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.3726C>A; p.Tyr1242a, c.3675C>G; p.Tyr1225a, c.3675C>G; p.Tyr1225a Family Information: 145 individuals with a DICER1 germline mutation and 135 controls from 48 families Case: family members used; both males and females used and no significant differences seen among sex; ages range from 20-40 with carriers being significantly younger than controls; no significant differences seen among ethnicity but participants located from the US, UK, and Great Britain CasePresentingHPOs: thyroid cancer or MNG diagnosis common to those with a DICER! mutation but with no chemotherapy or radiation treatment yet CasePreviousTesting: tested levels of thyroid-stimulating hormone, thyroxine, thyroxine-binding globulin, and serum albumin; thyroid palpation; thyroid ultrasound; Sanger or next-generation sequencing assays gnomAD: n/a Mutation Type: missense
Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder.
gene name: DICER 1 PMID (PubMed ID): 33570641 HGNCID: n/a Inheritance Pattern: autosomal dominant Disease Entity: benign and malignant tumor mutation Mutation: somatic Zygosity: heterozygous Variant: n/a Family Information: n/a Case: people of all sexes, ages, ethnicities and races participated CasePresentingHPOs: individuals with DICER1-associated tumors or pathogenic germline DICER1 variants were recruited to participate CasePreviousTesting: n/a gnomAD: n/a
Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations.
HGNCID:
Covid-19: Efficacité vaccinale. (2021, October 11). EPI-PHARE. https://www.epi-phare.fr/rapports-detudes-et-publications/impact-vaccination-covid-octobre-2021/
Times, T. N. Y. (2020, March 3). Coronavirus in the U.S.: Latest Map and Case Count. The New York Times. https://www.nytimes.com/interactive/2021/us/covid-cases.html
Schlosser, F. (2021, November 29). Omicron—Import Risk. Covid-19 Mobility Project. https://www.covid-19-mobility.org/reports/importrisk_omicron/
Kai Kupferschmidt. (2021, December 1). @DirkBrockmann But these kinds of models do help put into context what it means when certain countries do or do not find the the variant. You can find a full explanation and a break-down of import risk in Europe by airport (and the people who did the work) here: Https://covid-19-mobility.org/reports/importrisk_omicron/ https://t.co/JXsYdmTnNP [Tweet]. @kakape. https://twitter.com/kakape/status/1466109304423993348
Kai Kupferschmidt. (2021, December 1). @DirkBrockmann That percentage number tells you “how likely an infected passenger from South Africa or Botswana travels to each country and exits the airport there”. So: “0.9% in Germany means that out of 1000 such individuals, 9 are expected to have Germany as their final destination.” [Tweet]. @kakape. https://twitter.com/kakape/status/1466107478807097354
🇺🇦 Meaghan Kall. (2022, January 27). NEW: 🏴 Vaccine effectiveness (symptomatic infection) data for BA.2 {Omicron’s more infectious sister} NO difference in VE between Omicron (BA.1) and BA.2 Possibly even higher VE for BA.2 but estimates overlap See full thread 🧵 from @freja_kirsebom https://t.co/bJ7uCn2cGV [Tweet]. @kallmemeg. https://twitter.com/kallmemeg/status/1486821549458001927
Tom Wenseleers. (2022, January 23). @HarrySpoelstra @trvrb @CorneliusRoemer @JosetteSchoenma BA.2 has a growth rate advantage over BA.1 of ca 0.11/day. That’s quite sizeable. If it would have the same short generation time as BA.1 of 2.2 days it would imply a ca.1.3x higher transmissibility, due to higher contagiousness or immune escape. Https://t.co/X8TcWJ4pXQ [Tweet]. @TWenseleers. https://twitter.com/TWenseleers/status/1485375883066101763
Shalin Naik [@shalinhnaik]. (2021, October 14). 📢The first episode of the @thejabgab http://thejabgab.com is LIVE!! 🎙 Join me and the fabulous comedians @nazeem_hussain and @calbo as they chat about the Delta variant, vaccines …. And cows? With experts @DrKGregorevic and @BedouiSammy! Search your fav platform or... Https://t.co/bo4HiRfqF6 [Tweet]. Twitter. https://twitter.com/shalinhnaik/status/1448510610837159939
ReconfigBehSci [@SciBeh]. (2021, November 1). RT @HJWesteneng: Growth advantage and extrapolation of AY.4.2 based on Sanger Institute data in the UK (multilevel multinomial model). Base… [Tweet]. Twitter. https://twitter.com/SciBeh/status/1455467011509731332
Dr Dominic Pimenta [@DrDomPimenta]. (2021, December 15). An illustration of communicating risk with “less severe” variants: [Thread] Assume Omicron is 4x more transmissible than Delta. [1] Assume Omicron leads to 1/3 less admissions than Delta. [Figure below] Assume 1 in 100 cases of Delta are admitted to hospital. Https://t.co/XtnVwoOrUo [Tweet]. Twitter. https://twitter.com/DrDomPimenta/status/1471094002808242177
The DICER1 syndrome is an autosomal dominant tumor‐predisposi-tion disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer
GeneName:DICER1 PMID (PubMed ID): PMCID: PMC6418698 PMID: 30672147 HGNCID: NOT LISTED<br /> Inheritance Pattern: Autosomal Dominant Disease Entity: Cancer; benign and malignant tumors including pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig cell tumors, multinodular goiter, Thryoid cancer, rhabdomyosarcoma, and pineoblastoma. Mutation: Somatic missense variation Mutation type: missense Zygosity: None stated Variant: unregistered…. Family Information: Characterize germline variants in familial early-onset clorectal cancer patients; The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation. CasePresentingHPOs: uterine and rectal cancers in germline mutation
DICER1 syndrome is a rare genetic disorder that predisposes individuals to multiple cancer types.
GeneName = DICER1 PMID = 29762508 HGNCID = Can't find Inheritance pattern = Autosomal dominant Disease entity = cancer, multinodular goiter, pleuropulmonary blastoma, cystic nephroma, ovarian Sertoli-Leydig cell tumor Mutation = germline OR somatic Zygosity = causes loss of heterozygosity Variant = unregistered Family = those with the mutation almost always passed it on
ReconfigBehSci [@SciBeh]. (2021, November 26). RT @timcolbourn: @kallmemeg so no cases of B.1.1.529 cases in UK as of Mon 22nd Nov? Do you know when the S-gene drop out PCR results for… [Tweet]. Twitter. https://twitter.com/SciBeh/status/1464320681315905542
Pfizer and BioNTech Provide Update on Omicron Variant | Pfizer. (n.d.). Retrieved April 22, 2022, from https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-provide-update-omicron-variant
ReconfigBehSci [@SciBeh]. ‘RT @vikkypaedia: B.1.1.529 Seems to Have Gone from 0.1% to 50% in Just a Couple of Weeks, When It Took Delta Several Months to Achieve That…’. Tweet. Twitter, 26 November 2021. https://twitter.com/SciBeh/status/1464194450406752282.
ReconfigBehSci [@SciBeh]. ‘RT @Tuliodna: Busy Day on B.1.1.529 - a Variant of Great Concern - The World Should Provide Support to South Africa and Africa and Not Dis…’. Tweet. Twitter, 25 November 2021. https://twitter.com/SciBeh/status/1464130377178619904.
ReconfigBehSci [@SciBeh]. (2021, November 26). RT @macroliter: 👋Hi Journalists! Are you interested in covering the new B.1.1.529 #B11529 variant🦠? Here’s a link to a TABLE with the name… [Tweet]. Twitter. https://twitter.com/SciBeh/status/1464195246175272984
ReconfigBehSci [@SciBeh]. ‘RT @AdamJKucharski: Not a Thread, but Key Point: 6/6 Https://T.Co/LpCs46qSk6’. Tweet. Twitter, 25 November 2021. https://twitter.com/SciBeh/status/1464133953493815296.
The Guardian. ‘We Can Prevail over Omicron. We Just Need to Use the Tools We Have’, 1 December 2021, sec. Opinion. https://www.theguardian.com/commentisfree/2021/dec/01/we-can-prevail-over-omicron-use-tools-we-have.
Pérez-Then, E., Lucas, C., Monteiro, V. S., Miric, M., Brache, V., Cochon, L., Vogels, C. B. F., Cruz, E. D. la, Jorge, A., Santos, M. D. los, Leon, P., Breban, M. I., Billig, K., Yildirim, I., Pearson, C., Downing, R., Gagnon, E., Muyombwe, A., Razeq, J., … Iwasaki, A. (2021). Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: The Dominican Republic Experience (p. 2021.12.27.21268459). medRxiv. https://doi.org/10.1101/2021.12.27.21268459
Nathan Grubaugh [@NathanGrubaugh]. (2021, September 24). Hi @Newsweek 👋. I understand that #variant news has been slow recently with the near-complete dominance of Delta, but do you really need to go and make things up? Lineage R.1 is not a concern. Let me briefly explain why. (1/4) https://t.co/OD46PsXZEu [Tweet]. Twitter. https://twitter.com/NathanGrubaugh/status/1441522760832933888
Levine-Tiefenbrun, M., Yelin, I., Alapi, H., Katz, R., Herzel, E., Kuint, J., Chodick, G., Gazit, S., Patalon, T., & Kishony, R. (2021). Viral loads of Delta-variant SARS-CoV-2 breakthrough infections after vaccination and booster with BNT162b2. Nature Medicine, 1–3. https://doi.org/10.1038/s41591-021-01575-4
Morris, J. (2021, August 17). Israeli data: How can efficacy vs. severe disease be strong when 60% of hospitalized are vaccinated? Covid Data Science. https://www.covid-datascience.com/post/israeli-data-how-can-efficacy-vs-severe-disease-be-strong-when-60-of-hospitalized-are-vaccinated
Scott, national medical reporter S., & Thorne, the S. R. T. L. (2021, July 5). The Delta COVID variant is spreading overseas. Here’s why experts say it’s “absolutely essential” to protect children. ABC News. https://www.abc.net.au/news/2021-07-06/children-need-covid-protection-vaccines-experts-say/100269228
Sanderson, K. (2021). COVID vaccines protect against Delta, but their effectiveness wanes. Nature. https://doi.org/10.1038/d41586-021-02261-8
Carl T. Bergstrom. (2021, August 18). 1. There has been lots of talk about recent data from Israel that seem to suggest a decline in vaccine efficacy against severe disease due to Delta, waning protection, or both. This may have even been a motivation for Biden’s announcement that the US would be adopting boosters. [Tweet]. @CT_Bergstrom. https://twitter.com/CT_Bergstrom/status/1427767356600688646
Tao, K., Tzou, P. L., Nouhin, J., Gupta, R. K., de Oliveira, T., Kosakovsky Pond, S. L., Fera, D., & Shafer, R. W. (2021). The biological and clinical significance of emerging SARS-CoV-2 variants. Nature Reviews Genetics, 1–17. https://doi.org/10.1038/s41576-021-00408-x
Eric Topol. (2021, June 9). Despite increasing incentives, the US vaccination campaign is really struggling. Notably, the top 5 states are approaching 60% total population fully vaccinated which should provide strong protection vs the delta variant. A different story for the bottom 5 states @OurWorldInData https://t.co/boqk3Khhuc [Tweet]. @EricTopol. https://twitter.com/EricTopol/status/1402413221667954690
Adam Kucharski. (2021, March 11). New summary report on SARS-CoV-2 variants of concern and variants of interest in the UK: https://t.co/hJFljrN22E via @fact_covid https://t.co/43EYkfYzJO [Tweet]. @AdamJKucharski. https://twitter.com/AdamJKucharski/status/1370036245557051401
Carlos del Rio. (2021, April 7). U.K. variant now dominant form of COVID in US @CDCDirector As predicted B.1.1.7 is now the predominant SARS-CoV-2 strain in the US. Let’s remember it is much more transmissible and likely also more severe. Vaccines do cover it. @ajc https://t.co/Wc4oaYkxqR [Tweet]. @CarlosdelRio7. https://twitter.com/CarlosdelRio7/status/1379816377356333057
Hilda Bastian, PhD. (2021, February 6). Unofficial unnamed AstraZeneca insider says they are doing the interim analysis for the US trial of the Oxford vaccine. AstraZeneca spokesperson says 4-6 weeks till data release. Https://t.co/VUHgbHN02d One is wrong? Or they’ll release only when have FDA minimum follow-up? Https://t.co/LgjfX8AIti [Tweet]. @hildabast. https://twitter.com/hildabast/status/1357862227106095105
Alessandro Vespignani. (2021, April 14). “Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil”—P.1 may be 1.7–2.4-fold more transmissible—Previous (non-P.1) infection provides 54–79% of the protection against infection with P.1 that it provides against non-P.1 lineages https://t.co/aUpL4YOFYo https://t.co/YniaLb9YiF [Tweet]. @alexvespi. https://twitter.com/alexvespi/status/1382370044374511621
Joshua Weitz. (2021, April 7). The same approaches that work against SARS-CoV-2 work against variants like B.1.1.7: Mask Avoid indoor gatherings Socialize outdoors And, reinforces the need to continue to scale-up vaccine administration to all 16+. [Tweet]. @joshuasweitz. https://twitter.com/joshuasweitz/status/1379820197696180233
nature. (2021, April 16). Coronavirus variants: Where do they come from? How do we spot them? What do they mean for COVID vaccines, and future of the pandemic? Https://t.co/NRbORu2hoF [Tweet]. @Nature. https://twitter.com/Nature/status/1383093697374474240
Prof. Christina Pagel. (2021, December 29). Omicron was dominant everywhere in England by Christmas https://t.co/x58pJi7VcD [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1476161382852796419
Pan-Hammarström lab. (2022, January 7). Our new study: Heterogeneous vaccination strategy with inactivated vaccine + mRNA booster elicits strong B and T cell response against the WT and VOC including Omicron @VirusesImmunity https://t.co/aBiN9anMBL [Tweet]. @panhammarstrom. https://twitter.com/panhammarstrom/status/1479449892410044419
(20) Prof. Christina Pagel on Twitter: “THREAD (a bit delayed) on UK & covid: TLDR: flattish cases overall are masking differences between nations, regions & age groups. And we’re still out of whack with Europe. 1/20” / Twitter. (n.d.). Retrieved October 4, 2021, from https://twitter.com/chrischirp/status/1443261013911085056
Anthony J Leonardi, PhD, MS. (2022, January 23). Calling all GBD fans, your continued reinfection loyalty card. Nice one, @PeteUK7 https://t.co/AEMpdI5sr9 [Tweet]. @fitterhappierAJ. https://twitter.com/fitterhappierAJ/status/1485260239557509128
ReconfigBehSci. (2021, March 8). RT @rozeggo: New study on mortality of B.1.1.7 using health records from England. We found the variant of concern (VOC) was 1.67x more like… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1369567353722310657
ReconfigBehSci. (2021, May 7). RT @kallmemeg: The @PHE_uk Variant Technical Briefing 10 now published Confirms B.1.617.2 upgraded to a VOC due to transmissibility conce… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1391209724285050883
ReconfigBehSci. (2021, February 9). RT @ChristoPhraser: Our paper on evaluating the first three months of the NHS COVID-19 app is out now as a pre-print. A 🧵 1/n https://t.co/… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1359132102927798275
ReconfigBehSci on Twitter: ‘RT @AJWhisky: Missed this yesterday, but excellent once again from John. Largely reassuring on B.1.617.2 as things stand https://t.co/GtgJ…’ / Twitter. (n.d.). Retrieved 21 May 2021, from https://twitter.com/SciBeh/status/1391201750758031362
Prof. Christina Pagel. (2021, May 3). THREAD: Update on B.1.617 (‘India’) variant in England using latest data from the Sanger institute. This data excludes sequenced cases from travellers & surge testing so ‘should be an approximately random sample of positive tests in the community’ TLDR: warning signs! 1/10 https://t.co/0UzhM8GNIA [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1389273187586875396
ReconfigBehSci on Twitter: ‘RT @dgurdasani1: The bigger picture is sadly that we’re seeing rapid spread of B.1.617.2 among school age children in many parts of England…’ / Twitter. (n.d.). Retrieved 16 August 2021, from https://twitter.com/SciBeh/status/1396887312059944962
(1) ReconfigBehSci on Twitter: ‘RT @ScottGottliebMD: The U.K. is experiencing a growing surge of COVID infections with a new variant that appears more pathogenic, and that…’ / Twitter. (n.d.). Retrieved 21 June 2021, from https://twitter.com/SciBeh/status/1402048528189300737
BU Epi COVID Response Corps. (2021, February 17). We’ve seen so many vaccine questions, we did two videos! Here’s part 1 of our vaccine FAQ: https://t.co/gYASlhiwmm [Tweet]. @EpiCOVIDCorps. https://twitter.com/EpiCOVIDCorps/status/1362099096102854657
Denise Dewald, MD 🗽. (2021, August 12). Here are some modeling predictions for the delta variant from COVSIM (group at North Carolina State): PLEASE CHECK THIS OUT - RESOURCES TO SHARE WITH YOUR SCHOOL DISTRICT School-level COVID-19 Modeling Results for North Carolina for #DeltaVariant https://t.co/zU5hB9bKlY [Tweet]. @denise_dewald. https://twitter.com/denise_dewald/status/1425626289399009288
Prof. Shane Crotty. (2021, October 15). And here https://t.co/aDPrQ17AUD [Tweet]. @profshanecrotty. https://twitter.com/profshanecrotty/status/1449030846711681025
Prof. Christina Pagel. (2021, May 23). LONG THREAD on B.1.617.2 & latest PHE data covering: 1) latest tech report on B.1.617.2 (aka ‘India’ variant) 2) vaccine efficacy against B.1.617.2 3) consequences for roadmap 4) avoidability... Or not. [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1396574267349872644
Marc Lipsitch. (2021, July 20). At the risk of boiling down too much and certainly losing some detail, one way to summarize this wonderful thread is that when we think about vaccine effectiveness, we should think of 4 key variables: 1 which vaccine, 2 age of the person, 3 how long after vax, 4 vs what outcome. [Tweet]. @mlipsitch. https://twitter.com/mlipsitch/status/1417595538632060931
Prof. Christina Pagel 🇺🇦. (2021, November 25). THREAD on the new variant B.1.1.529 summarising what is known from the excellent South African Ministry of Health meeting earlier today TLDR: So much uncertain but what is known is extremely worrying & (in my opinion) we should revise red list immediately. This is why: 1/16 [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1463885539619311616
BNO/Medriva Newsroom [@medriva]. (2021, November 26). South Africa’s health minister says, based on a small sample of Omicron cases, the majority of hospital patients are unvaccinated: ‘It indicates that the vaccines are providing protection’ [Tweet]. Twitter. https://twitter.com/medriva/status/1464327805836083201
3 big questions about the Biden administration’s COVID response in 2022. (2021, December 30). PBS NewsHour. https://www.pbs.org/newshour/health/3-big-questions-about-the-biden-administrations-covid-response-in-2022
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