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MED13L-related intellectual disability due to paternal germinal mosaicism
Beáta Bessenyei1, István Balogh1, Attila Mokánszki2
1Division of Clinical Genetics, Department of Laboratory Medicine, University of Debrecen, Debrecen, 4032 Hungary.
Abstract:
The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common forms of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications, or sequence variants has been identified as deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and being the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. Thirty-two subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.
Insights
Paternal germinal mosaicism for a MED13L variant is identified as a cause of MRFACD syndrome, a form of intellectual disability. This finding expands understanding of genetic inheritance patterns for this condition.
Area of Science:
- Genetics
- Developmental Biology
- Human Genetics
Background:
- MED13L-related intellectual disability, or MRFACD syndrome, is a common syndromic intellectual disability.
- It is characterized by intellectual disability, hypotonia, motor and speech delays, and distinct facial features.
- De novo MED13L gene disruptions (deletions, duplications, sequence variants) are known causes.
Observation:
- A case of paternal germinal mosaicism for a MED13L missense variant is presented.
- This mosaicism led to MRFACD syndrome in one child and likely intellectual disability and facial dysmorphism in another sibling.
- This is the first reported instance of germinal mosaicism for MED13L causing this syndrome.
Findings:
- Paternal germinal mosaicism for a MED13L missense variant can cause MRFACD syndrome.
- This genetic mechanism explains the occurrence of the syndrome in multiple offspring from a single parent.
- The findings highlight the importance of considering germinal mosaicism in syndromic intellectual disability cases.
Implications:
- This study expands the known genetic mechanisms for MED13L-related intellectual disability.
- It underscores the role of the Mediator complex in transcriptional regulation and congenital malformations (transcriptomopathies).
- Recognizing germinal mosaicism is crucial for accurate genetic counseling and recurrence risk assessment in affected families.
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