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

Abstract

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MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

“…[7,[34][35][36]41,42] Additionally, it presents with a wide spectrum of developmental delay and intellectual disability, pulmonary abnormalities, diaphragmatic issues, and intestinal malrotation. [41,[43][44][45][46][47][48] Many aspects of these developmental processes remain incompletely understood, and the causes of abnormal development are not well-established. A pathogenic variant of MYRF is also associated with neurological conditions characterized by extensive myelin vacuolization, reflecting similar findings observed in mice where Myrf plays a crucial role in regulating myelination.…”

“…The individuals exhibit underdevelopment or incomplete development in lungs, known as pulmonary hypoplasia, where they fail to reach their typical size and do not form the required number of air sacs (alveoli) and blood vessels. [7,40,41,45,48] This can lead to diminished lung function and insufficient oxygenation of the blood. Additionally, the cartilage walls of the bronchial tubes within the lungs can weaken or collapse, narrowing the airways and causing breathing difficulties.…”

“…The spectrum of cardiovascular anomalies is extensive, with Scimitar syndrome being a commonly reported condition. [7,40,41,43,44,46,48] This syndrome is characterized by an abnormal placement and structure of the pulmonary veins. Instead of connecting to the left atrium as expected, one or more pulmonary veins from the right lung drain into the inferior vena cava or the right atrium.…”

“…In the case of 46,XX individuals with MYRF-CUGS, they are less commonly reported and tend to display atypical internal genitalia, which can include the absence of a uterus, fallopian tubes, small or absent ovaries, absent vagina, or a blind-ending vagina. [41,46,48] Heart and vasculature…”

“…Individuals with MYRF-CUGS may exhibit a condition known as Congenital Diaphragmatic Hernia (CDH), which arises when the diaphragm fails to close properly during fetal development, resulting in a hole. [7,36,40,41,45,47,48,52] This opening in the diaphragm allows abdominal organs to protrude into the chest cavity, potentially leading to underdeveloped lungs and respiratory difficulties after birth due to compression and displacement of the developing lungs. Another condition that affects the diaphragm is Diaphragmatic Eventration, which can be caused by abnormal elevation or weakness of one side of the diaphragm.…”