Dataset Information

Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

ABSTRACT:

Background

Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations.

Case presentation

We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance.

Conclusions

To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

SUBMITTER: Slaba K

PROVIDER: S-EPMC10178803 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

Slaba Katerina K Jezova Marta M Pokorna Petra P Palova Hana H Tuckova Jana J Papez Jan J Prochazkova Dagmar D Jabandziev Petr P Slaby Ondrej O

Molecular genetics & genomic medicine 20230125 5

<h4>Background</h4>Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital car ...[more]

PMID: 36695166

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Project description:BackgroundGenetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism.MethodsThree adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects.ResultsAll three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects.ConclusionIndividuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population.

Dataset Information

Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

Background

Case presentation

Conclusions

Publications

Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

Similar Datasets

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