Table 1 Clinical characteristics of patients with FLNC-associated RCM and congenital myopathy
Pt1 | Pt2 | Pt3 | Pt4 | Pt5 | Pt6 | Pt7 | Pt8 | Pt9 | Pt10 | Pt11 | Pt 12 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Gender | f | m | f | m | m | f | m | m | m | m | m | m |
Genotype | chr7: 128485066-7:GC > CT NM_001458: A1183L rs1131692185 | chr7: 128485076:C > T NM_001458: A1186V rs1114167361 | chr7: 128485076:C > T NM_001458: A1186V rs1114167361 | chr7: 128485076: C > T NM_001458: A1186V rs1114167361 | chr7: 128485076:C > T NM_001458: A1186V rs1114167361 | chr7: 128489034: 4926_4927del NM_001458: splice cite loss − | chr7: 128494628: G > A NM_001458: V2297M rs1420394583 | chr7: 128485076: C > T NM_001458: A1186V rs1114167361 | chr7: 128485076: C > T NM_001458: A1186V rs1114167361 | chr7: 128497173: 75 bp del NM_001458: V2522_S2546del − | chr7: 128493858: G > A NM_001458: G2151S − | chr7: 128494598: A > C NM_001458: T2287P |
ACMG classification | P (PS3, PM1, PM2, PP3, PP4) | P (PS2, PS3, PM1, PM2, PP3, PP4) | P (PS3, PM1, PM2, PP3, PP4) | P (PS2, PS3, PM1, PM2, PP3, PP4) | P (PS2, PS3, PM1, PM2, PP3, PP4) | P (PVS1, PS2, PM2, PP3) | LP (PM1, PM2, PP2, PP3, PP5) | P (PS2, PS3, PM1, PM2, PP3, PP4) | P (PS2, PS3, PM1, PM2, PP3, PP4) | P (PVS1, PS2, PM2, PP3) | LP (PM1, PM2, PP3, PP4) | LP (PM1, PM2, PP3, PP4) |
Mutation status | − | De novo | − | − | De novo | − | Maternal | De novo | De novo | De novo | − | − |
Initial symptoms initiated clinical contact | Slow weight gain, dyspnea | Weakness | Slow weight gain | Slow weight gain, ECG signs of enlarged atria | Arthrogryphosis at birth. Inappropriate sinus tachycardia at 6 min walk at age 15 led to first cardiac visit | Echo in 6 month—ASD | Echo in neonatal period—ASD | Stiff neck (Klippel-Feil-like), hypertonus from birth | Arthrogryposis (fixed pronation position, unable to supinate) | Echo in 6 month—VSD | Echo in neonatal period—muscle VSD Echo in 2 y.o.—atrial dilatation | 4 month—Slow Weight Gain, Dyspnea. Echo in 6 month—multiple VSDs, CoA |
Age of NM presentation | At birth | At birth | During first year | During first year | At birth joint contractures | During first year | During first year | At birth | At birth | During first year | During first year | 4 month |
Family history | − | − | − | − | − | − | + (mother-RCM, AF) | − (insignificant ventricular extrasystoles in the mother) | + (mother, RF ablation for arrhythmia) | − | − | − |
Cardiomyopathy phenotype | RCM/HCM ASD | RCM ASD | RCM ASD | RCM VSD | RCM | RCM ASD | RCM | RCM | RCM | RCM VSD | RCM, muscle VSD | RCM, multiple VSDs, Aortic Arch hypoplasia |
Age of cardiomyopathy diagnosis | 6 months | 1.2 y.o | 3 years | 1 y.o | 15 y o | 3 y.o | 3 y.o | 3.5 y.o | 2 y.o | 6 months | at birth | 6 months |
Conduction disturb | RBBB | RBBB | RBBB | − | AV block I | RBBB | RBBB | AV block I, RBBB | − | RBBB | RBBB | RBBB, AV block 1 |
SVT/AF | + (1 paroxysm SVT) | − | − | + (1 paroxysm SVT) | − | − | + (AF) | − | − | − | − | − |
VT | − | − | − | − | − | − | − | − | − | − | − | − |
SCD | − | − | − | − | − | − | − | − | − | − | − | − |
Htx list/performed | +/− | − | − | − | +/+ | − | +/− | − | − | − | − | − |
Cardiac Enzymes | ↑CK-MB × 2 ↑Troponin × 1.5 | ↑CK-MB × 2–4 Normal Troponin | ↑CK-MB × 2 Normal Troponin | ↑CK-MB × 2.5 Normal Troponin | ↑CK-MB × 1.5 Troponin n/a | Normal CK-MB Normal Troponin | ↑CK-MB × 1.5 Normal Troponin | ↑ CK-MB × 2.1 Troponin n/a | Normal CK-MB Troponin n/a | ↑CK-MB × 1.16 Normal Troponin | Normal CK-MB Normal Troponin | Normal CK-MB Normal Troponin |
NT-proBNP | ↑ × 83 (10,434 pg/mL) | ↑ × 25 (3157 pg/mL) | ↑ × 50 (6279 pg/mL) | ↑ × 21 (3116 pg/mL) | n/a | ↑ × 7 (1019 pg/mL) | ↑ × 17 (2174 pg/mL) | n/a | n/a | ↑ × 7 (1030 pg/mL) | ↑ × 40 (4986 pg/mL) | ↑ × 19 (3724 pg/mL) |
Cardiac MRI | Not performed | Not performed | The pericardium is not changed. Severe dilatation of both atria; ventricles are not dilated. LV ejection fraction at the lower limit of the norm. No clear pathological contrast delay | The pericardium is not changed. Severe dilatation of both atria; ventricles are not dilated. LV ejection fraction is normal. On delayed post-contrast images in the mid-apical part of the antero-septal region, minimally pronounced intramural fibrous changes are determined | Not performed | Not performed | The pericardium is not changed. The right atrium is dilated, the left atrium is moderately dilated, the ventricles are not dilated. No clear pathological contrast delay agent in the LV myocardium | Not performed | Not performed | The MRI picture may correspond to a non-compact LV myocardium. Dilation of the LA. On delayed post-contrast images in the basal parts of the antero-septal region, minimally pronounced intramural fibrous changes are determined | Not performed | Not performed |
Limb-girdle weakness | + | + | + | − | + | − | + | + | − | − | − | + |
Distal muscle weakness | − | + | − | − | − | + | − | − | − | − | − | + |
Difficulty toe walking | + | − | − | − | − | + | − | + (with difficulties) | − | − | − | − |
Winged scapulas | − | + | + | − | − | + | + | + | + | + | − | + |
Facial weakness | − | + | + | − | − | − | + | + | − | − | + | − |
Ptosis | − | + | − | − | − | − | + | − | − | − | − | − |
Camptodactyly | − | − | − | − | − | + (5th fingers) | + | − | − | − | − | − |
Inability to Rise from squatting Position | + | + | + | − | − | − | − (balance problems) | − | − | − | − | |
Arthrogryposis | + (at birth) | + (at birth) | − | − | + (at birth) | − | − | + | + | − | − | + |
Scoliosis | − | + | + (severe progressive) | − | + (severe, progressive—> scoliosis surgery) | − | + | + | − | − | + | − |
Pectus deformation | − | Pectus excavatum | − | − | − | − | − | Pectus carinatum | − | − | − | − |
Hip dysplasia | + | + | + | − | − | + | − | + | − | − | − | − |
Torticollis | − | − | − | − | − | + | + | + | − | − | − | − |
Joint contracture | − | + | − | + | + Marked contractures shoulders. Mild contractures hips, ankles, index toes, elbows, wrists, right thumb | + (Ankle stifness) | − | + | + (forearm) | + (Ankle stifness) | − | − |
Hernia | White line hernia | Umbilical hernia | White line hernia | − | − | − | − | − | − | − | + | Umbilical hernia |
Other | Microsomia | − | Microsomia | Growth retardation. Pes equinus Long QT | Muscle biopsy: centrally located nuclei. Cytoplasmic body myopathy | Short stature of mixednesis; Hypoglycemia, long QT | Periorbital cyanosis | Sprengler deformity, Noonan-like phenotype | Micromandibula, short neck, hyperkyphosis, pedes plani, undescended testes | Presyncope, Long QT | − | Microsomia, Pulmonary hypertension, coagulopathy, Diffuse non-toxic goiter, subclinical hypothyroidism |
CNS | − | Pyramid insufficiency Clonical seizures | − | Pyramid insufficiency | − | − | − | − | − | − | − | |
ENMG | Diffuse myopathic pattern | Diffuse myopathic pattern Neuropathy | Diffuse myopathic pattern | Sensory polyneuropathy in the legs and arms | Not performed | Diffuse sensory neuropathy | − | Normal | − | Normal | − | Diffuse myopathic pattern |
Muscle Enzymes | Normal CK ↑LDH × 1.5 | ↑CK × 1.5–4 ↑LDH × 1.5 | ↑CK × 1.2 ↑LDH × 1.5 | ↑CK × 1.32 ↑LDH × 1.84 | Transaminases normal | Normal CK ↑LDH × 1.45 | Normal CK Normal LDH | ↑CK × 2.8, ↑LDH × 1.4, ↑myoglobin × 1.8 | ↑CK × 3.8 normal myoglobin & LDH | Normal CK Normal LDH | Normal CK Normal LDH | Normal CK ↑LDH × 1.15 |
Outcome | Listed for HTx at 3 y.o | Death at 2 years of age | Death at 9 years of age | HTx at 18 y.o | Listed for HTx at 12 y.o | ICD |