Somatic mosaicism contributes to phenotypic variation in Timothy syndrome

Etheridge, Susan P.; Bowles, Neil E.; Arrington, Cammon B.; Pilcher, Thomas A.; Rope, Alan F.; Wilde, Arthur A.M.; Alders, Mariëlle; Saarel, Elizabeth V.; Tavernier, René; Timothy, Katherine W.; Tristani‐Firouzi, Martin

doi:10.1002/ajmg.a.34223

Cited by 67 publications

(62 citation statements)

References 15 publications

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“…1,7 Given these findings, it is clear that mosaicism contributes to the inheritance of TS1. Although we acknowledge this is not the first case in which a parent harboring limited presence of the canonical TS1 mutation has been affected by syndactyly alone, without any cardiac phenotype, this is the first case in which the diagnosis of this potentially lethal disorder was confounded by mosaicism.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies of mosaicism in Klinefelter' s syndrome have shown that mosaicism may affect the germline preferentially, with a mutation frequency of ,10% in blood lymphocytes and .36% in the gametes. 7 This observation, coupled with the fact that commercial genetic testing was unable to detect low-level CACNA1C-G406R mosiacism, suggests that a negative test result in the parent(s) of children with rare genetic disorders associated with germline mosiacism should be viewed with healthy skepticism, as these tests are optimized to detect heterozygous mutations (ie, 50% allelic frequency), rather than the low frequency (ie, ,10%) of the mutant allele present in the lymphocyte-derived gDNA of mosaic individuals. As such, clinicians may consider additional testing, particularly in cases in which an overlapping phenotype is observed, when using genetic test results to help parents make informed family planning decisions.…”

Section: Discussionmentioning

confidence: 99%

“…C, TS1 mutation (p.G406R, c.1216 G.A) causes the loss of a splice site on exon 8a for the restriction enzyme AciI. 7 The mother' s digested DNA shows a faint mutant band (outlined in yellow). and average age of death of 2.5 years for TS1 individuals.…”

Section: Figurementioning

confidence: 99%

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Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome

Dufendach¹,

Giudicessi

Boczek

et al. 2013

Pediatrics

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome

Dufendach¹,

Giudicessi

Boczek

et al. 2013

Pediatrics

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“…To date, only 32 TS cases have been reported worldwide. [12][13][14] In this study, we identified the first case of TS in Chinese by genetic analysis and explored potential drug therapies for this malignant syndrome. The major novel findings of our study include: (1) a uncommon mosaicism in both germline and partial somatic inheritance for the CACNA1C-G406R mutation in TS; (2) worsening of functional 2:1 AVB and TWA in TS by use of either propranolol (a β-adrenergic receptor blocker) or diltiazem (a calcium channel blocker); and (3) abolishment of 2:1 AVB and TWA in TS by mexiletine via inhibition of I Na,L .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Late Sodium Current by Mexiletine

Gao

Xue

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background-Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A(TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an I Na blocker, mexiletine, to improve clinical manifestations in TS. Methods and Results-A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening.Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father's oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470-490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT-RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late I Na with IC 50 of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT-RR slope in the TS model using BayK 8644. Conclusions-Mexiletine shortened QTc, attenuated QT-RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late I Na . (Circ Arrhythm Electrophysiol. 2013;6:614-622.)Key Words: atrioventricular block ◼ late sodium current ◼ LQT8 ◼ mexiletine ◼ T wave alternans ◼ Timothy syndrome

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“…All previously described cases of TS-1 are associated with a missense mutation in exon 8A (p.G406R) of the Ltype calcium channel gene (Ca(v)1.2, CACNA1C). Most people reported in the literature represent highly affected individuals who present early in life with severe cardiac and neurological manifestations, but these authors found somatic mosaicism in TS-1 patients with less severe manifestations than the typical TS-1 patient [153]. There are therefore likely large ascertainment biases, given that people with much less expressive phenotypes are likely not coming to anyone's attention.…”

Section: "Those Who Have Given Any Attention To Congenital Mental Lesmentioning

confidence: 99%