Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome

Abstract

The presence of 2 distinct populations of somatic or germline cells within a single individual harboring different genotypes is termed mosaicism. Recent reports suggest that parental mosaicism is involved in the heritability of type 1 Timothy syndrome (TS1), an extremely rare and life-threatening multisystem disorder characterized by severe QT interval prolongation, syndactyly, and several other complications. Although full TS1 is caused by a single missense mutation in the CACNA1C-encoded cardiac calcium channel, mosaic TS1 parents can display isolated syndactyly without additional phenotypic manifestations. A newborn boy presented with syndactyly at birth. The presence of syndactyly in his mother led to a diagnosis of benign familial syndactyly. However, at 9 months of age, during his first syndactyly-corrective surgery, intraoperative electrocardiograms revealed extreme QT prolongation and 2:1 atrioventricular block. A comprehensive cardiac evaluation was performed, and both mother and child were tested genetically, confirming a clinical suspicion of TS1. Only the patient tested positive for the TS1 mutation; however, more extensive molecular testing revealed a limited presence of the mutation in maternally-derived DNA. This case illustrates the potential of parental mosaicism to confound the diagnosis of potentially life-threatening genetic diseases, such as TS1. Here, a mother with a partial TS1 phenotype and genetically confirmed mosaicism transmitted the TS1-causative mutation to her son, resulting in fully expressive TS1. Thus, a shared partial phenotype should not be dismissed as a benign or insignificant finding, but should be evaluated further to rule out the possibility of parental mosaicism concealing a potentially fatal heritable disease.

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome

“…Single channel analysis of both kinds of TS mutants 479 revealed, that they opened longer and more frequently[24,25], mainly 480 resulting from slowed and decreased voltage-dependent inactivation 481[26].482Gain-of-function mutations in Cav1.2 were for a long time exclusive-483 ly linked to TS[6,14]. In addition to germline mutations, mosaic forms 484 have also been noted in patients with a partial or restricted phenotype 485[27][28][29]. Recently, a gain-of-function mutation in CACNA1C was identi-486 fied in a familial LQTS in the absence of TS signs[30].…”

Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1

“…Prenatal drugs could affect the QTc interval of the fetus [Kies et al, 2005], and such exposure could be contributor for fetal hydrops in our patient in relation with the referred use of amitriptyline during the first 4 months of pregnancy, since this tricyclic antidepressant is associated with a significant increase in the QTc interval [van Noord et al, 2009]. Additionally, in at least two patients, the TS1 was diagnosed incidentally from a severe cardiac event during anesthetic process for syndactyly-corrective surgery Dufendach et al, 2013].…”

“…Although a de novo mutation was assumed in our patient because the molecular and the EKG and echocardiographic evaluations were normal in both parents, a parental mosaicism cannot be excluded because the family history of syndactyly and unspecified congenital cardiac defects can be suggestive of this, but no further studies were unfortunately completed. Thus, our genetic counseling is limited because there is somatic mosaicism molecularly confirmed in TS1, inclusive with variable expression and vertical transmission [Dufendach et al, 2013;Etheridge et al, 2011]. This is the second report of a patient with TS1 where the arrythmogenic manifestation leads to fetal hydrops [Lo-A-Njoe et al, 2005, patient B].…”

Calcium Channel Mutations in Cardiac Arrhythmia Syndromes

“…This suggests that mutation arose during development after specification of cardiomyocytes, and she was able to transmit the mutation only because she did not suffer life-threatening arrhythmias. Four additional mosaicism subjects have subsequently been documented 1112 . Only one had a prolonged QT interval.…”