title: 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.
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Dufendach
authors.forename: John R
authors.initials: JR
authors.lastname: Giudicessi
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D001321:Autistic Disorder; D003937:Diagnosis, Differential; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009030:Mosaicism; D009035:Mothers; D009154:Mutation; D013576:Syndactyly / Q000175:diagnosis / Q000235:genetics*
keywords: Timothy syndrome; long QT syndrome; mosaicism; syndactyly