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Molecular Diagnostics Laboratory

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DDC Clinic Genetic Testing Reveals Novel Cause of Overgrowth and Intellectual Disability

DDC Clinic Genetic Testing Reveals Novel Cause of Overgrowth and Intellectual Disability

Submitted by cwensel on Mon, 02/13/2017 - 12:40

There are more than a dozen overgrowth and intellectual disability syndromes. The majority of the overgrowth syndromes are familial, inherited in an autosomal dominant pattern. Tatton-Brown-Rahman syndrome was described in 2014 with all reported cases due to a de novo mutation within the DNMT3A gene. 

Our recent publication in Clinical Genetics summarizes two families for whom Tatton-Brown-Rahman syndrome is familial with multiple affected siblings. In one Amish family of four affected children and multiple unaffected children, the unaffected Amish father was found to be heterozygous for the pathogenic DNMT3A variant. Due to his unaffected status, further analysis of DNA from multiple tissues was initiated and revealed that this father is mosaic for the DNMT3A variant. All of the affected children were positive in every tested tissue and none of the unaffected children tested positive for the variant in any tested tissue. The paternal grandparents were also tested using DNA from multiple tissues and no copy of the variant was detected, confirming the de novo nature of the DNMT3A variant in this father. The second family is French Canadian and includes two affected children, now adult, multiple unaffected siblings and unaffected parents. Testing of multiple tissues for the mother was negative for the familial DNMT3A variant but genetic testing was not possible for the deceased father.

Important lessons learned, or relearned:

  • Normal parents with affected children does not equal autosomal recessive inheritance, even (or especially) in a population such as Amish or French Canadian which has a high incidence of disorders due to founder mutations.
  • Recurrence risk estimates for an unknown disorder must include the possibility that one parent is an unaffected mosaic for an autosomal dominant disorder.
    • The recurrence risk quoted for a de novo nonfamilial autosomal dominant variant is just a few percent while the recurrence risk with one unaffected but mosaic parent is up to 50%.

Responding to our finding for the first family resulted in the inclusion of the DNMT3A gene on our Overgrowth and Intellectual Disabilities NGS Panel. This enabled us to provide the genetic diagnosis for the second family. DDC Clinic Molecular Diagnostics Laboratory (DDC Clinic Lab) continues to use our research findings to aid in diagnostic genetic testing.

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