Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects

Gerarda Cappuccio, Nicola Brunetti‐Pierri, Paul Clift, Christopher Learn, John C. Dykes, Catherine L. Mercer, Bert Callewaert, Ilse Meerschaut, Alessandro Mauro Spinelli, Irene Bruno, Matthew J. Gillespie, Aaron T. Dorfman, Adda Grimberg, Mark E. Lindsay, Angela E. Lin

Research output: Contribution to journalArticlepeer-review

Abstract

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.
Original languageEnglish
Pages (from-to)1384-1395
Number of pages12
JournalAmerican Journal of Medical Genetics Part A
Volume188
Issue number5
DOIs
Publication statusPublished - May 2022

Bibliographical note

Funding Information:
Wellcome Sanger Institute, Grant/Award Number: WT098051; Wellcome and the Department of Health; Health Innovation Challenge Fund, Grant/Award Number: HICF‐1009‐003 Funding information

Funding Information:
The authors are grateful to the individuals and families with Myhre syndrome, supportive colleagues, and to the Myhre Syndrome Foundation who have supported our research. They acknowledge the role of geneticist Louisa C. Pyle, MD, PhD in diagnosing Patient 5. This study was in part generated within the European Reference Network ITHACA. The authors thank Dr Julie Vogt from Birmingham Women's and Children's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham for confirmation of the trio WES result in Patient 3 who had participated in the Deciphering Developmental Disorders (DDD) research study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Funding Information:
The authors are grateful to the individuals and families with Myhre syndrome, supportive colleagues, and to the Myhre Syndrome Foundation who have supported our research. They acknowledge the role of geneticist Louisa C. Pyle, MD, PhD in diagnosing Patient 5. This study was in part generated within the European Reference Network ITHACA. The authors thank Dr Julie Vogt from Birmingham Women's and Children's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham for confirmation of the trio WES result in Patient 3 who had participated in the Deciphering Developmental Disorders (DDD) research study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF‐1009‐003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Publisher Copyright:
© 2022 Wiley Periodicals LLC.

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