Genetics in Medicine (2022) 24, 2204–2205
www.journals.elsevier.com/genetics-in-medicine
LETTER TO THE EDITOR
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:
We read with great interest the article by Nizon et al, in1
which the authors have described a cohort of 7 unrelated
individuals with intellectual disability/developmental delay
and loss-of-function variants in MED12L gene. The
phenotype was characterized by intellectual disability/
developmental delay (7/7), speech and motor impairment
(7/7), seizures (1/7), gastrointestinal anomalies (5/7), facial
and hand dysmorphic signs (5/7), and callosal dysgenesis
(2/4). All probands had a germline loss-of-function variant
in MED12L gene, and the pathogenic variant was de novo in
4 of 4 patients. This condition was named Nizon-Izidor
syndrome (OMIM 618872). To the best of our knowledge,
no other patients with this condition were published in the
literature.
Herein we report on a male proband with a de novo
germline variant in MED12L. The proband showed mild
motor and speech delay, oligodontia, and dysmorphic signs.
Surprisingly this patient also carried 2 de novo chromosomal
balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),
t(5;9)(p15;q21). The chromosomal rearrangements were
confirmed using fluorescence in situ hybridization with whole
chromosome painting probes. Array-comparative genomic
hybridization resulted normal: arr(1-22)x2 (XY)x1. Exome
sequencing revealed a frameshift variant in heterozygosis in
MED12L gene: NM_053002.6 (MED12L_v001):c.971del;p.
(pro324Glnfs*18). This sequence variant is previously
undescribed in population databases. Genotyping of the par-
ents revealed that it is a de novo variant. The sequence vari-
ation was considered probably pathogenic (category 4,
American College of Medical Genetics and Genomics).
Surprisingly, 1 of the 7 probands described by Nizon et al1
also carried a balanced reciprocal translocation (individual
5: 46,XY,t9p13;18q12.2).
MED12L gene is part of the kinase domain of the
Mediator complex, which is involved in chromatin
regulation and chromosome structural maintenance.
Mediator is composed of 4 different modules (kinase,
head, middle, and tail) and transfers information from
proteins bound at DNA response elements to the RNA
polymerase 2 transcription machinery.1 MED12L in-
teracts with NACP2, a non-structural maintenance of
chromosomes gene and is part of condensin I complex
that regulates chromosomal segregation in early
mitosis.2-4 Hypomorphic ncapd2 mice show abnormal
anaphase bridges, and these phenomena were also
observed in cultured fibroblasts from individuals with
NCAPD2 germline variants.5 Green et al6 also observed
chromosomal anaphase bridges in chicken cells lacking
condensing function. More recently, Zhang et al7
showed that RNA polymerase 2 is essential for re-
establishing chromatin architecture upon re-entry in to
G1 phase. In the absence of RNA polymerase 2 com-
plex, loop extrusion and longer chromatin loops were
observed.8
We believe that the finding of 2 balanced translocations
in our proband, who is also a heterozygote for a loss-of-
function variant in MED12L, may not be coincidental.
Instead, it might be the result of chromosomal instability
generated by the MED12L loss-of-function variant. The
breakpoints of the observed translocations are different, and
do not correlate with MED12L gene locus, favoring the
hypothesis that they may be the result of some form of
chromosomal instability.
For these reasons, we believe that the presence of 2
reciprocal translocations in our proband might actually be
the result of some form of chromosomal instability and
represent a phenotypic trait associated with loss-of-function
variants in MED12L. If this holds true, then genotyping of
MED12L should be performed in carriers of multiple and/or
complex de novo translocations (balanced or unbalanced),
as well as in heterozygotes of germline pathogenic variants
Letter to the Editor
in genes related to the kinase module of the Mediator
complex (MED12, MED12L, MED13, MED13L, CycC,
CDK8, CDK19). In addition, karyotyping of cultured
fibroblasts from these patients may reveal additional mitotic
abnormalities.
Data Availability
The data are available upon request.
Ethics Declaration
The study was approved by a single Institutional Review
Board, UNIRIO – Hospital Universitário Gaffrée e Guinle /
HUGG-UNIRIO, under the number 53449321.0.0000.5258,
according to the Declaration of Helsinki. The written
informed consent signed by the parent was received and
archived by the authors.
Conflict of Interest
The authors declare no conflicts of interest.
Marina Kossmann Ferraz1,2
Ana Carolina Esposito1
Cláudio Schmidt3
Maria Angélica Lima1
Fernando Regla Vargas1,4,*
1 6. Green LC, Kalitsis P, Chang TM, et al. Contrasting roles of condensin I
Medical Genetics Service, Gaffrée and Guinle University Hospital,
Universidade Federal do Estado do Rio de Janeiro,
Rio de Janeiro, Brazil
2
D’Or Institute of Research and Education (IDOR),
Rio de Janeiro, Brazil
3
Centro de Genética Médica do Rio de Janeiro, Rio de Janeiro, Brazil
4 transcription. Nat Rev Mol Cell Biol. 2015;16(3):155–166. http://doi.org/
Birth Defects Epidemiology Laboratory, Oswaldo Cruz Institute,
Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
2205
*Correspondence and requests for materials should be addressed to
Fernando Regla Vargas, Birth Defects Epidemiology Laboratory,
Oswaldo Cruz Institute, Fundação Oswaldo Cruz, Room 617,
Pav Leônidas Deane, Av Brasil 4365, 21040-360, Rio de Janeiro,
RJ, Brazil.
E-mail address: fernando.vargas@ioc.fiocruz.br
Received 20 May 2022; Accepted 23 May 2022
Available online 4 August 2022
© 2022 American College of Medical Genetics and Genomics.
Published by Elsevier Inc. All rights reserved.
http://doi.org/10.1016/j.gim.2022.05.019
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