Table 3.
Variants with uncertain impact on stroke are shown, which we characterized as additional findings.
| Clinical and genetic findings in 27 patients with variants in genes with possible impact on stroke but no evidence of a monogenetic stroke disease or with class 5 variants not explaining ischemic stroke | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical Information | Genetic Information | ||||||||||||
| Age | TOAST | Sex | Additional phenotypic features | Gene | Inheritance | Phenotype generally associated | Genotype | c.DNA | AAC | Transcript | ACMG | MAF | |
| I | 53 | 5 | m |
Sclerosed aortic valve, No cardiomyopathy |
TNNI3 | AD | Hypertrophic Cardiomyopathy | Het | c.497C > T | p.Ser166Phe | NM_000363.5 | 5 | 0.0001 |
| 33 | 5 | f |
Long-QT syndrome Follow-up event recorder: Sinus rhythm |
KCNQ1 | AD | Atrial Fibrillation, Long-QT | Het | c.1588C > T | p.Gln530Ter | NM_000218.2 | 5 | 0.0001 | |
| II | 47 | 5 | f |
Hb: 11.2 g/dl Thrombocytes: 271 G/l |
JAK2 | Somatic, AD | Polycythemia vera | Het | c.3188G > A | p.Arg1063His | NM_00492.4 | 3 | 0.0047 |
| 55 | 3 | m |
Hb: 15.1 g/dl Thrombocytes: 283 G/l |
Somatic, AD | Polycythemia vera | Het | c.3188G > A | p.Arg1063His | NM_00492.4 | 3 | 0.0047 | ||
| 53 | 1 | m |
Hb: 16.9 g/dl Thrombocytes: 288 G/l |
Somatic, AD | Polycythemia vera | Het | c.3188G > A | p.Arg1063His | NM_00492.4 | 3 | 0.0047 | ||
| 34 | 5 | m | COL4A1 | AD | Cerebral Small Vessel Disease | Het | c.4970C > T | p.Thr1657Met | NM_01845.6 | 3 | 0.0001 | ||
| 54 | 3 | m | NOTCH3 | AD | CADASIL | Het | c.5129G > A | p.Gly1710Asp | NM_000435.3 | 3 | 0.0005 | ||
| 51 | 4 | m | ICA Dissection | COL5A1 | AD | Ehlers-Danlos, classic type, Fibromuscular Dysplasia | Het | c.4307C > T | p.Pro1436Leu | NM_000093.5 | 3 | 0.0001 | |
| III | 55 | 1 | m |
High-grade stenosis of the ICA left. Moderate stenosis of contralateral ICA CVRF: moderate AHT |
RNF213 | Susceptibility gene | Moyamoya Disease | Het | c.12055C > T | p.Arg4019Cys | NM_001256071.3 | 2/3 | 0.0010 |
| 42 | 5 | m | ABCC6 | AR | Pseudoxanthoma elasticum | Het | c.3421C > T | p.Arg1141Ter | NM_001171.6 | 5 | 0.0014 | ||
| 55 | 2 | f | AR | Pseudoxanthoma elasticum | Het | c.1171A > G | p.Arg391Gly | NM_001171.6 | 5 | 0.0056 | |||
| 44 | 5 | m | AR | Pseudoxanthoma elasticum | Het | c.1232A > G | p.Asn411Ser | NM_001171.6 | 5 | 0.0001 | |||
| 37 | 5 | f |
Strokes in all territories, PFO shown by TEE Prot. S activity not measured |
PROS1 | AD/AR | Thrombophilia due to Protein S deficiency | Het | c.233C > T | p.Thr78Met | NM_000313.4 | 4 | 0.0002 | |
| IV | 47 | 5 | m | HDL: 41 mg/dl | ABCA1 | AR | Tangier Disease | Het | c.5398A > C | p.Asn1800His | NM_005502.4 | 5 | 0.0007 |
| 46 | 5 | f | HDL: 48 mg/dl | AR | Tangier Disease | Het | c.5398A > C | p.Asn1800His | NM_005502.4 | 5 | 0.0007 | ||
| 54 | 5 | f | HDL: 33 mg/dl (–) | AR | Tangier Disease | Het | c.5398A > C | p.Asn1800His | NM_005502.4 | 5 | 0.0007 | ||
| 52 | 1 | m | HDL 32 mg/dl (–) | AR | Tangier Disease | Het | c.1196 T > C | p.Val399Ala | NM_005502.4 | 4/5 | 0.0037 | ||
| 44* | 4 | m |
Moyamoya Disease Cholesterol 174 mg/dl HDL 25 mg/dl (–) |
AR | Tangier Disease | Het | c.6083C > T | p.Ala2028Val | NM_005502.4 | 3 | 0.0002 | ||
| * | APOB | AD | Hypercholesterolemia, familial | Het | c.13288 T > A | p.Ser4430Thr | NM_000384.3 | 3 | 0.0001 | ||||
| 41 | 5 | m | Cholesterol 221 mg/dl (+) | AD | Hypercholesterolemia, familial | Het | c.5269C > G | p.Leu175Val | NM_000384.3 | 3 | 0.0001 | ||
| 53 | 3 | m | Cholesterol 228 mg/dl (+) | AD | Hypercholesterolemia, familial | Het | c.689G > C | p.Gly230Ala | NM_000384.3 | 3 | 0.0001 | ||
| 55 | 1 | m | Cholesterol 228 mg/dl (+) | AD | Hypercholesterolemia, familial | Het | c.11401 T > A | p.Ser3801Thr | NM_000384.3 | 3 | 0.0012 | ||
| 35 | 1 | m | Cholesterol 166 mg/dl, Triglycerides 314 mg/dl (+), HDL 18 mg/dl (–) | LPL | AD | Combined Hyperlipidemia, familial | Het | c.953A > G | p.Asn318Ser | NM_000237.3 | 3 | 0.0145 | |
| 50 | 1 | f | Cholesterol 361 mg/dl (+), Triglycerides 780 mg/dl (+), LDL 127 mg/dl (+), HDL 42 mg/dl | AD | Combined Hyperlipidemia, familial | Het | c.953A > G | p.Asn318Ser | NM_000237.3 | 3 | 0.0145 | ||
| 55 | 5 | m | Cholesterol 213 mg/dl (+), Triglycerides 261 mg/dl (+), LDL 150 mg/dl (+), HDL 30 mg/dl (–) | AD | Combined Hyperlipidemia, familial | Het | c.953A > G | p.Asn318Ser | NM_000237.3 | 3 | 0.0145 | ||
| 48 | 5 | f | Cholesterol 209 mg/dl (+), Triglycerides 164 mg/dl, LDL 164 mg/dl (+), HDL 30 mg/dl (–) | AD | Combined Hyperlipidemia, familial | Het | c.953A > G | p.Asn318Ser | NM_000237.3 | 3 | 0.0145 | ||
| 52 | 5 | m | Cholesterol 258 mg/dl (+), Triglycerides 287 mg/dl (+), LDL 188 mg/dl (+), HDL 40 mg/dl | AD | Combined Hyperlipidemia, familial | Het | c.953A > G | p.Asn318Ser | NM_000237.3 | 3 | 0.0145 | ||
| 51 | 1 | m | Cholesterol 191 mg/dl, Triglycerides 200 mg/dl, LDL 145 mg/dl (+), HDL 33 mg/dl (–) | AD | Combined Hyperlipidemia, familial | Het | c.286G > A | p.Val96Leu | NM_000237.3 | 3/4 | 0.0001 | ||
Genetic information on the variant detected as well as clinical information on the patient are depicted. Additional findings were divided into four subgroup as depicted in the results
ACMG American college of medical genetics, ACMG 5 pathogenic, ACMG 4 likely pathogenic, ACMG 3 variant of unknown significance, ACMG 2 likely benign, AAC Amino acid change, AD autosomal dominant, Age Age at first stroke event, AHT arterial hypertension, c.DNA coding position, Cholesterol target value < 190 mg/dl, FH Family History, Hb Hemoglobin standard value depending on sex from 12 to 18 g/dl, HDL High Density Lipoprotein Cholesterol with a standard value 35–65 mg/dl, Het. heterozygous, Hom. homozygous, ICA Internal Carotid Artery, LDL Low Density Lipoprotein Cholesterol with a target value < 100 mg/dl, MAF Minor allele frequency according to gnomAD, MB Micro bleeds, MRI Magnetic resonance imaging characteristics, n/a not available in gnomAD, TEE transesophageal echocardiography, TOAST Classification of Stroke etiology according to the international Trial of Org 10172 in Acute Stroke Treatment criteria, TOAST 1 large-artery atherosclerosis, TOAST 2 cardioembolism, TOAST 3 small-vessel occlusion, TOAST 4 stroke of other determined etiology, TOAST 5 stroke of undetermined etiology, Triglycerides target value < 200 mg/dl, Thrombocytes G/l 109/l standard value 150–450 G/l, WMH White matter hyperintensities, * = same patient with multiple variants, (+) = elevated compared to target value, (–) lowered compared to target value.