CaseV-4: Female, 11 years old
DiseaseAssertion: CFTD and LVNC
FamilyInfo: Multigenerational Italian family. Phenotypic data were available for 10 individuals (3 males and 7 females) ranging in age from 4 to 50 years old. All individuals were of Caucasian ancestry. DNA was available for 6 individuals (IV-10, IV-13, IV-14, V-1, V-4, V-5). Authors identified a mild LVNC phenotype in the mother (IV-14), sister (V-5) and cousin (V-1) of the proband, with hypertabeculations of the mid inferolateral wall and of the ape and without neuromuscular disorders. During the growth, there was a reduction of clinical signs in patients V-1 and V-5. No data have been collected for individual IV-9, who died at the age of 35 of unknown causes. The father (IV-13) of the proband was asymptomatic.
Proband is the first child of a family with a history of consanguinity (mother’s parents are first-degree cousins) and diabetes in the maternal line (grandmother, one great-uncle, one uncle and a first-degree cousin) without neuromuscular diseases.
LVNC segregated as a dominant mode of inheritance with high phenotypic heterogeneity and reduced penetrance. CFTD phenotype showed a recessive mode of inheritance.
CasePresentingHPOs: HP:0001290, HP:0002033, HP:0001643, HP:0001655, HP:0001374, HP:0004325, HP:0001943, HP:0001508, HP:0002515, HP:0002650, HP:0001284
"Generalized hypotonia, poor suck, Patent ductus arteriosus, Patent foramen ovale, Congenital hip dislocation, Decreased body weight (below 3rd percentile), Hypoglycemia, Failure to thrive, waddling gait, Scoliosis, Areflexia
CaseHPOFreeText: persistent crying, Persistent arterial duct and patent foramen ovale were diagnosed at birth but resolved spontaneously, as shown by echocardiography at the age of 1 month, congenital dislocation of the left hip, at 17 months of age hospitalized due to body weight below the third percentile and hypoglycemia, difficulties in chewing and swallowing, inability to stand up from a sitting position, a slight degree of weakness of the facial and masticator muscles, mild weakness of the glutei and ileo-psoas and marked bilateral quadriceps, Tendon reflexes were absent. Joints contractures had never been observed, A blood test confirmed hypoglycemia and normal levels of serum creatine kinase and isoenzymes, quadriceps muscle biopsy displayed a predominance of type 1 fibers
CaseNotHPOs:
CaseNotHPOFreeText: internal nuclei, nemaline bodies, cores were observed
CasePreviousTesting: Authors extended the clinical and instrumental (EMG, ECG, Echocardiography, muscle biopsy) evaluation to the whole family, Echocardiography showed a slight left ventricular (LV) dilatation, a moderate reduction of the LV global function (ejection fraction 40%), and a non-compacted aspect of the overall infero-lateral wall. The karyotype and FISH were normal. The serum creatine kinase (CK) was within the normal range, Dystrophin, emerin, calpain and lamin A/C were examined and found to be normal, cardiological investigation confirmed a long QTc and showed signs of left ventricular hypertrophy and repolarization abnormalities in the ECG, performed a thorough survey of all previously identified CFTD and LVNC genes to definitively exclude their involvement in the disease phenotype. Only intronic polymorphic variants were detected in TPM3, ACTA1, TPM2, MYL2, MYL3, G4.5, DTNA, ZASP, ACTC1, MYBPC3 and TMP1. Both intronic and coding polymorphic variants were detected in SEPN1, RYR1, MYH7, LMNA/C, TNNT2 and TNNI3
GenotypingMethod: Whole-exome sequencing of the proband and her cousin
VariantMYH7B: NM_020884.5:c.2668C>T
ClinVar:
CAID: CA9827409
gnomAD: https://gnomad.broadinstitute.org/variant/20-33582046-C-T