Maternal mosaicism confounds the neonatal diagnosis of type 1 timothy syndrome

Keith A. Dufendach, John R. Giudicessi, Nicole J. Boczek, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 lifethreatening 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.

Original languageEnglish (US)
Pages (from-to)e1991-e1995
Issue number6
StatePublished - Jun 2013


  • Long QT syndrome
  • Mosaicism
  • Syndactyly
  • Timothy syndrome

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


Dive into the research topics of 'Maternal mosaicism confounds the neonatal diagnosis of type 1 timothy syndrome'. Together they form a unique fingerprint.

Cite this