Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Linda Z. Rossetti, Kevin Glinton, Bo Yuan, Pengfei Liu, Nishitha Pillai, Elizabeth Mizerik, Pilar Magoulas, Jill A. Rosenfeld, Lefkothea Karaviti, Vernon R. Sutton, Seema R. Lalani, Daryl A. Scott

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.

Original languageEnglish (US)
Pages (from-to)1376-1382
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number7
StatePublished - Jul 2019
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank family members for participating in this research. This work was funded in part by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD; R01 HD093660 to DAS).

Publisher Copyright:
© 2019 Wiley Periodicals, Inc.


  • MYRF
  • congenital diaphragmatic hernia
  • congenital heart defects
  • myelin regulatory factor
  • pulmonary hypoplasia
  • urogenital anomalies


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