This letter discusses a male patient found to have a de novo loss-of-function variant in the MED12L gene as well as two de novo balanced reciprocal translocations. The authors believe finding these chromosomal rearrangements in addition to the MED12L variant is not coincidental, but rather suggests the variant may cause a form of chromosomal instability. They note one of the patients in the original study also had a balanced translocation. The authors argue MED12L genotyping should be considered for others with multiple/complex de novo translocations or known pathogenic MED12L variants.
This letter discusses a male patient found to have a de novo loss-of-function variant in the MED12L gene as well as two de novo balanced reciprocal translocations. The authors believe finding these chromosomal rearrangements in addition to the MED12L variant is not coincidental, but rather suggests the variant may cause a form of chromosomal instability. They note one of the patients in the original study also had a balanced translocation. The authors argue MED12L genotyping should be considered for others with multiple/complex de novo translocations or known pathogenic MED12L variants.
This letter discusses a male patient found to have a de novo loss-of-function variant in the MED12L gene as well as two de novo balanced reciprocal translocations. The authors believe finding these chromosomal rearrangements in addition to the MED12L variant is not coincidental, but rather suggests the variant may cause a form of chromosomal instability. They note one of the patients in the original study also had a balanced translocation. The authors argue MED12L genotyping should be considered for others with multiple/complex de novo translocations or known pathogenic MED12L variants.
Correspondence on “Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect” by Nizon et al To the Editor: regulation and chromosome structural maintenance. We read with great interest the article by Nizon et al, in1 Mediator is composed of 4 different modules (kinase, which the authors have described a cohort of 7 unrelated head, middle, and tail) and transfers information from individuals with intellectual disability/developmental delay proteins bound at DNA response elements to the RNA and loss-of-function variants in MED12L gene. The polymerase 2 transcription machinery.1 MED12L in- phenotype was characterized by intellectual disability/ teracts with NACP2, a non-structural maintenance of developmental delay (7/7), speech and motor impairment chromosomes gene and is part of condensin I complex (7/7), seizures (1/7), gastrointestinal anomalies (5/7), facial that regulates chromosomal segregation in early and hand dysmorphic signs (5/7), and callosal dysgenesis mitosis.2-4 Hypomorphic ncapd2 mice show abnormal (2/4). All probands had a germline loss-of-function variant anaphase bridges, and these phenomena were also in MED12L gene, and the pathogenic variant was de novo in observed in cultured fibroblasts from individuals with 4 of 4 patients. This condition was named Nizon-Izidor NCAPD2 germline variants.5 Green et al6 also observed syndrome (OMIM 618872). To the best of our knowledge, chromosomal anaphase bridges in chicken cells lacking no other patients with this condition were published in the condensing function. More recently, Zhang et al7 literature. showed that RNA polymerase 2 is essential for re- Herein we report on a male proband with a de novo establishing chromatin architecture upon re-entry in to germline variant in MED12L. The proband showed mild G1 phase. In the absence of RNA polymerase 2 com- motor and speech delay, oligodontia, and dysmorphic signs. plex, loop extrusion and longer chromatin loops were Surprisingly this patient also carried 2 de novo chromosomal observed.8 balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22), We believe that the finding of 2 balanced translocations t(5;9)(p15;q21). The chromosomal rearrangements were in our proband, who is also a heterozygote for a loss-of- confirmed using fluorescence in situ hybridization with whole function variant in MED12L, may not be coincidental. chromosome painting probes. Array-comparative genomic Instead, it might be the result of chromosomal instability hybridization resulted normal: arr(1-22)x2 (XY)x1. Exome generated by the MED12L loss-of-function variant. The sequencing revealed a frameshift variant in heterozygosis in breakpoints of the observed translocations are different, and MED12L gene: NM_053002.6 (MED12L_v001):c.971del;p. do not correlate with MED12L gene locus, favoring the (pro324Glnfs*18). This sequence variant is previously hypothesis that they may be the result of some form of undescribed in population databases. Genotyping of the par- chromosomal instability. ents revealed that it is a de novo variant. The sequence vari- For these reasons, we believe that the presence of 2 ation was considered probably pathogenic (category 4, reciprocal translocations in our proband might actually be American College of Medical Genetics and Genomics). the result of some form of chromosomal instability and Surprisingly, 1 of the 7 probands described by Nizon et al1 represent a phenotypic trait associated with loss-of-function also carried a balanced reciprocal translocation (individual variants in MED12L. If this holds true, then genotyping of 5: 46,XY,t9p13;18q12.2). MED12L should be performed in carriers of multiple and/or MED12L gene is part of the kinase domain of the complex de novo translocations (balanced or unbalanced), Mediator complex, which is involved in chromatin as well as in heterozygotes of germline pathogenic variants