A novel 2.3 Mb microduplication of 12q24.21q24.23 detected by genome-wide tiling-path resolution array comparative genomic hybridization in a girl with syndromic mental retardation

Ruiter, Mariken; Koolen, David A.; Pfundt, Rolph; Leeuw, Nicole de; Klinkers, Harry M J; Sistermans, Erik A.; Veltman, Joris A.; Vries, Bert B.A. de

doi:10.1097/01.mcd.0000220605.94413.bb

Cited by 11 publications

(7 citation statements)

References 24 publications

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“…A larger de novo duplication of 2.3 Mb spanning 12q24.21q24.23 containing 16 genes together with MED13L has been reported in a girl with syndromic ID without cardiac abnormality. 12 However, several of these affected genes are expressed in the brain and/or are involved in embryogenesis and thus, it is likely that a combination effect of them is contributing to their patient's phenotype. Of note, there are two further de novo CNVs affecting MED13L in the DECIPHER database, including a gain of 60 kbp within exons 5-28 in a female patient with ID, developmental delay, auricular tags and macrostomia (DECIPHER no.…”

Section: Discussionmentioning

confidence: 99%

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

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Section: Discussionmentioning

confidence: 99%

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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“…The so‐called “reversed” symptoms, microcephaly, and short stature are consistent findings in the duplication but they are not specific. There are many other chromosomal imbalances, including microduplications, that are associated with microcephaly [Lisi et al, ] or short stature [Ruiter et al, ].…”

Section: Discussionmentioning

confidence: 99%

The phenotypic spectrum of duplication 5q35.2–q35.3 encompassing NSD1: Is it really a reversed sotos syndrome?

Dikow

Maas

Gaspar

et al. 2013

American J of Med Genetics Pt A

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Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID). Microduplications of 5q35.2-q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyotyping. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause.

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“…Also, in several cases of postnataly diagnosed duplication 12q corpus callosum anomalies (hypoplasia, partial agenesis) and foot malformations have been described 4,5 . Phenotypic contribution of monosomy 2q37.3 cannot be excluded in our cases, but based on literature review of case reports with pure duplications involving 12q24 region we believe that described anomalies are more consistent with partial trisomy 12q [6][7][8][9] .…”

Section: Discussionmentioning

confidence: 75%

Prenatal ultrasonographic manifestations of partial trisomy 12q(12q24.2→qter) and partial monosomy 2q (2q37.3→qter)

et al. 2020

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A novel 2.3 Mb microduplication of 12q24.21q24.23 detected by genome-wide tiling-path resolution array comparative genomic hybridization in a girl with syndromic mental retardation

Cited by 11 publications

References 24 publications

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

The phenotypic spectrum of duplication 5q35.2–q35.3 encompassing NSD1: Is it really a reversed sotos syndrome?

Prenatal ultrasonographic manifestations of partial trisomy 12q(12q24.2→qter) and partial monosomy 2q (2q37.3→qter)

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