An Additional Individual with a De Novo Variant in Myelin Regulatory Factor (MYRF) with Cardiac and Urogenital Anomalies: Further Proof of Causality: Comments on the article by Pinz et al. ()

Chitayat, David; Shannon, Patrick; Uster, Tami; Nezarati, Marjan M.; Schnur, Rhonda E.; Bhoj, Elizabeth

doi:10.1002/ajmg.a.40360

Cited by 19 publications

(27 citation statements)

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“…MYRF is also expressed outside of the central nervous system, and there is increasing evidence that it plays a critical role in the development of various organs including the heart, lungs, diaphragm, and genitourinary tract [Chitayat et al, 2018;Homsy et al, 2015;Jin et al, 2017;Nagase et al, 1999;Pinz et al, 2018;Qi et al, 2018;Stohr et al, 2000]. Pinz et al described two males with scimitar syndrome [MIM# 106700] and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis who were found to have likely pathogenic variants in MYRF [Pinz et al, 2018].…”

Section: Introductionmentioning

confidence: 99%

“…Pinz et al described two males with scimitar syndrome [MIM# 106700] and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis who were found to have likely pathogenic variants in MYRF [Pinz et al, 2018]. Chitayat et al then described a male fetus with hypoplastic left heart sequence, atretic/dysplastic aortic, mitral, and tricuspid valves, hypoplasia of the ascending aorta, total anomalous pulmonary venous connection to the right atrium, mild pulmonary hypoplasia, intestinal malrotation, and ambiguous genitalia who also had a likely pathogenic variant in MYRF [Chitayat et al, 2018]. Based on these reports, a new genetic syndrome, cardiac-urogenital syndrome [MIM# 618280], was defined.…”

Section: Introductionmentioning

confidence: 99%

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Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Rossetti

Glinton

Yuan

et al. 2019

American J of Med Genetics Pt A

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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 (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 congenital heart defects, 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

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Rossetti

Glinton

Yuan

et al. 2019

American J of Med Genetics Pt A

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“…Мієлін-регуляторний фактор (MYRF) відіграє значну роль у регулюванні формування та підтримці мієлінізації в центральній нервовій системі як під час розвитку, так і в дорослому віці [32,33]. Нещодавно проведені дослідження показали, що de novo мутації гена MYRF асоційовані з вродженою діафрагмальною килою, серцевими аномаліями, зокрема синдромом Шімітара, урогенітальними аномаліями та енцефалопатією [34][35][36][37][38]. Один з двох наших пацієнтів з мутацією MYRF p.N105D був зареєстрований в чоловічій статі і не мав екстрагенітальних проявів, у той час як інша -фенотипова дівчинка з MYRF c.2572+1G>A, що вперше звернулася до ендокринолога у віці 14 років з приводу первинної аменореї, мала тяжку гіперметропію та амбліопію обох очей.…”

Section: мутації в гені Amhr2unclassified

Genetic spectrum of disorders of sex development in children in Ukraine

Globa¹,

Зелінська²,

Shcherbak³

et al. 2019

CE&ES

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“…The MYRF gene encodes a membrane protein that is subject to autocleavage, releasing a transcription factor protein fragment that stimulates expression of genes important for myelination of CNS nerve fibers. [6] Variants in MYRF had been previously associated with cardiac defects (scimitar syndrome, dextrocardia), [7][8][9] urogenital malformations [7][8][9], diaphragmatic hernia [9], and encephalopathy. [10] In 2019, 10 unique MYRF variants were detected in nanophthalmos patients, including 9 that cause premature termination of translation via frameshifts due to insertions, deletions, splicing defects, or nonsense variants [2,3,5].…”

Section: Introductionmentioning

confidence: 99%

Nanophthalmos patient with a THR518MET mutation in MYRF, a case report

et al. 2020

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Background Nanophthalmos has a significant genetic background and disease-causing mutations have been recently been reported in the myelin regulatory factor (MYRF) gene. We report clinical features in a patient with nanophthalmos and a Thr518Met MYRF mutation. Case presentation A three-year-old male was discovered to have nanophthalmos after first presenting to the emergency department for a frontal headache, eye pain, emesis, and lethargy. Imaging studies (CT and MRI) were negative except for increased posterior fossa cerebrospinal fluid. Subsequent examinations revealed nanophthalmos (short axial eye lengths 18.1 mm OD and 18.3 mm OS), microcornea, and a large crystalline lens. Peripheral chorioretinal pigment abnormalities were also observed. He experienced episodes of marked ocular hypertension (53 mmHg OD and 60 mmHg) likely due to intermittent angle closure precipitated by nanophthalmos. The ocular hypertension was responsive to topical medicines. Genetic analysis of known nanophthalmos genes MFRP and TMEM98 were negative, while a novel mutation, Thr518Met was detected in MYRF. The Thr518Met mutation was absent from 362 matched normal controls and was extremely rare in a large population database, allele frequency of 0.000024. The Thr518Met mutation altered a highly conserved amino acid in the MYRF protein and three of four algorithms suggested that this mutation is likely pathogenic. Finally, molecular modeling showed that the Thr518Met mutation is damaging to MYRF structure. Together these data suggest that the Thr518Met mutation causes nanophthalmos. Conclusions Nanophthalmos may present at an early age with features of angle closure glaucoma and a Thr518Met mutation in MYRF was detected in a patient with nanophthalmos. Prevalence data, homology data, mutation analysis data, and protein modeling data suggest that this variant is pathogenic and may expand the phenotypic range of syndromic nanophthalmos caused by MYRF mutations to include central nervous system abnormalities (increased posterior fossa cerebrospinal fluid).

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An Additional Individual with a De Novo Variant in Myelin Regulatory Factor (MYRF) with Cardiac and Urogenital Anomalies: Further Proof of Causality: Comments on the article by Pinz et al. ()

Cited by 19 publications

References 1 publication

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF

Genetic spectrum of disorders of sex development in children in Ukraine

Nanophthalmos patient with a THR518MET mutation in MYRF, a case report

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