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Review
. 2019 Jul;179(7):1376-1382.
doi: 10.1002/ajmg.a.61182. Epub 2019 May 8.

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Linda Z Rossetti  1 , Kevin Glinton  1 , Bo Yuan  1   2 , Pengfei Liu  1   2 , Nishitha Pillai  1 , Elizabeth Mizerik  1 , Pilar Magoulas  1 , Jill A Rosenfeld  1 , Lefkothea Karaviti  3 , Vernon R Sutton  1 , Seema R Lalani  1 , Daryl A Scott  1   4
Affiliations
Review

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Linda Z Rossetti et al. Am J Med Genet A. 2019 Jul.

Abstract

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.

Keywords: MYRF; congenital diaphragmatic hernia; congenital heart defects; myelin regulatory factor; pulmonary hypoplasia; urogenital anomalies.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Genetics. Otherwise, authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. The heterozygous de novo c.3118A>G, p.(Arg1040Gly) missense variant in MYRF seen in Subject 1 affects a conserved amino acid and may also affect splicing.
A) The arginine at position 1040 is conserved down to mice. B) The c.3118A>G change occurs close to the exon 23/intron 23 junction and is predicted to disrupt the associated donor splice site.
Figure 2
Figure 2. The locations of the variants in MYRF are shown in relation to its protein domains.
MYRF variants identified in Subjects 1–3 (S1–3) are shown in red. Variants previously reported in individuals with congenital anomalies affecting the heart, lungs, diaphragm and genitourinary system are shown in black. The variant that has been shown to cause mild encephalitis/encephalopathy with reversible myelin vacuolization (MIM# 618113) is shown in blue. Stop-gain, frameshift (shown above the protein) and variants that could affect splicing are located throughout MYRF. Based on their locations, these variants are likely to trigger nonsense-mediated mRNA decay. In contrast, single amino acid changes (shown below the protein) are clustered in the DNA binding domain and the peptidase S74 domain.
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