Recurrent Third-Trimester Fetal Loss and Maternal Mosaicism for Long-QT Syndrome

Background—The importance of germ-line mosaicism in genetic disease is probably underestimated, even though recent studies indicate that it may be involved in 10% to 20% of apparently de novo cases of several dominantly inherited genetic diseases. Methods and Results—We describe here a case of repeated germ-line transmission of a severe form of long-QT syndrome (LQTS) from an asymptomatic mother with mosaicism for a mutation in the cardiac sodium channel, SCN5A. A male infant was diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks and with LQTS after birth, ultimately requiring cardiac transplantation for control of ventricular tachycardia. The mother had no ECG abnormalities, but her only previous pregnancy had ended in stillbirth with evidence of cardiac decompensation at 7 months’ gestation. A third pregnancy also ended in stillbirth at 7 months, again with nonimmune fetal hydrops. The surviving infant was found to have a heterozygous mutation in SCN5A (R1623Q), previously reported as a de novo mutation causing neonatal ventricular arrhythmia and LQTS. Initial studies of the mother detected no genetic abnormality, but a sensitive restriction enzyme–based assay identified a small (8% to 10%) percentage of cells harboring the mutation in her blood, skin, and buccal mucosa. Cord blood from the third fetus also harbored the mutant allele, suggesting that all 3 cases of late-term fetal distress resulted from germ-line transfer of the LQTS-associated mutation. Conclusions—Recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQTS-associated mutations, with important implications for genetic counseling.

[1]  M. Sanguinetti,et al.  Compound Mutations: A Common Cause of Severe Long-QT Syndrome , 2004, Circulation.

[2]  Hui Zhao,et al.  Prenatal diagnosis and in utero treatment of torsades de pointes associated with congenital long QT syndrome. , 2003, The American journal of cardiology.

[3]  S. Purcell,et al.  Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring , 2003, Journal of medical genetics.

[4]  A. Gramolini,et al.  Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death , 2003, Nature.

[5]  A. Wilde,et al.  The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome , 2003, Journal of medical genetics.

[6]  S. Chow,et al.  Prenatal diagnosis and treatment of fetal long QT syndrome: a case report , 2002, Prenatal diagnosis.

[7]  D. Tester,et al.  A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine. , 2002, Cardiovascular research.

[8]  J. Towbin,et al.  Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. , 2001, JAMA.

[9]  G. Breithardt,et al.  Molecular diagnosis in a child with sudden infant death syndrome , 2001, The Lancet.

[10]  G. Breithardt,et al.  De Novo Mutation in the SCN5A Gene Associated With Early Onset of Sudden Infant Death , 2001, Circulation.

[11]  J. Oldenburg,et al.  Somatic mosaicism in hemophilia A: a fairly common event. , 2001, American journal of human genetics.

[12]  M. Sanguinetti,et al.  Molecular and Cellular Mechanisms of Cardiac Arrhythmias , 2001, Cell.

[13]  G. Breithardt,et al.  Life-threatening Arrhythmias Genotype-phenotype Correlation in the Long-qt Syndrome : Gene-specific Triggers for Genotype-phenotype Correlation in the Long-qt Syndrome Gene-specific Triggers for Life-threatening Arrhythmias , 2022 .

[14]  A J Moss,et al.  Spectrum of Mutations in Long-QT Syndrome Genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 , 2000, Circulation.

[15]  S. Priori,et al.  A molecular link between the sudden infant death syndrome and the long-QT syndrome. , 2000, The New England journal of medicine.

[16]  M. Komajda,et al.  First description of germline mosaicism in familial hypertrophic cardiomyopathy , 2000, Journal of medical genetics.

[17]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[18]  A. Gorgels,et al.  The Long QT Syndrome with Impaired Atrioventricular Conduction: A Malignant Variant in Infants , 1998, Journal of cardiovascular electrophysiology.

[19]  E. Rosenthal,et al.  Prolongation of the QT interval and the sudden infant death syndrome. , 1998, The New England journal of medicine.

[20]  Joël Zlotogora,et al.  Germ line mosaicism , 1998, Human Genetics.

[21]  G. Breithardt,et al.  Genetic basis and molecular mechanism for idiopathic ventricular fibrillation , 1998, Nature.

[22]  B. Gallie,et al.  Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. , 1998, American journal of human genetics.

[23]  J. Balser,et al.  Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. , 1998, Circulation.

[24]  R. Matsuoka,et al.  A de novo missense mutation of human cardiac Na+ channel exhibiting novel molecular mechanisms of long QT syndrome , 1998, FEBS letters.

[25]  X. Estivill,et al.  Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. , 1995, American journal of human genetics.

[26]  P. Gillette,et al.  Infants with long-QT syndrome and 2:1 atrioventricular block. , 1995, American heart journal.

[27]  G. V. Van Hare,et al.  The Long QT Syndrome in Children An International Study of 287 Patients , 1993, Circulation.

[28]  M. Leppert,et al.  Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita , 1992, Neuron.

[29]  J. Haines,et al.  Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita , 1992, Cell.

[30]  F. Conti,et al.  Structural parts involved in activation and inactivation of the sodium channel , 1989, Nature.

[31]  P. Schwartz.  Cardiac sympathetic innervation and the sudden infant death syndrome. A possible pathogenetic link. , 1976, The American journal of medicine.

[32]  A. Covone,et al.  Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study , 2004, Human Genetics.

[33]  H. Yamagishi,et al.  Congenital Long QT Syndrome and 2:1 Atrioventricular Block with a Mutation of the SCN5A Gene , 2003, Pediatric Cardiology.

[34]  M. Furutani,et al.  A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT syndrome , 1998, Human mutation.

[35]  M. Raghunath,et al.  Gly802Asp Substitution in the proα2(I) Collagen Chain in a Family with Recurrent Osteogenesis imperfecta due to Paternal Mosaicism , 1996, European journal of human genetics : EJHG.