Homozygous missense mutation in<i>MED25</i>segregates with syndromic intellectual disability in a large consanguineous family

Figueiredo, Thalita; Melo, Uirá Souto; Pessoa, André Luiz Santos; Nóbrega, Paulo Ribeiro; Kitajima, João Paulo; Correa, Igor; Zatz, Mayana; Kok, Fernando; Santos, Silvana

doi:10.1136/jmedgenet-2014-102793

Cited by 26 publications

(20 citation statements)

References 37 publications

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“…Beside the ARCMT2B mutation, mutations in MED25 have been described in 2 other diseases: Basel-VanagaiteSmirin-Yosef syndrome (OMIM 616449) and syndromic intellectual disability [Basel-Vanagaite et al, 2015;Figueiredo et al, 2015]. Our patient shares many clinical features with the patients mentioned in these studies ( Table 1 ).…”

Section: Discussionsupporting

confidence: 57%

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COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants

Nair

Lama²,

El‐Hayek

et al. 2018

Mol Syndromol

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We report on a girl, born to first-cousin Lebanese parents, with severe intellectual disability, congenital hip luxation, cardiac malformation, short stature, facial dysmorphic features including microcephaly, sparse hair, bilateral epicanthal folds, ataxia, seizures, and elevated lactate and pyruvate levels in serum. Whole exome sequencing was carried out on the patient's DNA. Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found. The potential pathogenicity of these variants, and the possibility that the 2 variants could synergistically act to produce the phenotype reported, is discussed.

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Section: Discussionsupporting

confidence: 57%

“…MED25 was first implicated in the pathogenesis of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) [Leal et al, 2001[Leal et al, , 2009. However, recent studies suggest that the mutation implicated in CMT2B is likely to be a rare benign variant rather than pathogenic [Figueiredo et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants

Nair

Lama²,

El‐Hayek

et al. 2018

Mol Syndromol

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“…While this manuscript was under revision, an article was published on homozygous missense p.(Arg140Trp) mutation in MED25 in a large consanguineous family from Northeastern Brazil in which seven adults were diagnosed with syndromic intellectual disability (Figueiredo et al 2015). Facial features described in the present study, such as prognathism, prominent chin and very large and overhanging nose tip, were not observed in the affected individuals described in that article, possibly due to the evolvement of these features with age.…”

Section: Discussionmentioning

confidence: 50%

Homozygous MED25 mutation implicated in eye–intellectual disability syndrome

et al. 2015

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Genetic syndromes involving both brain and eye abnormalities are numerous and include syndromes such as Warburg micro syndrome, Kaufman oculocerebrofacial syndrome, Cerebro-oculo-facio-skeletal syndrome, Kahrizi syndrome and others. Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village. The protein encoded by MED25 belongs to Mediator complex or MED complex, which is an evolutionary conserved multi-subunit RNA polymerase II transcriptional regulator complex. The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.

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“…Exome reads were analyzed in a standard Bioinformatics pipeline using BWA for sequence alignment to the GRCh37 reference, Broad Institute GATK for genotyping, SnpEff for variant annotation and ExomeDepth for CNV detection. [12][13][14][15][16] Potentially deleterious variants detected in regions of homozygosity by descent, not present in 59 723 unrelated individuals from Exome Aggregation Consortium or in a Brazilian control population (1484 individuals) were selected for segregation analysis by Sanger sequencing. A 193-bp fragment harboring the candidate mutation was amplified using forward primer: 5′-CCATGAA CAGGAATGCAAAA-3′ and reverse primer: 5′-GGGATACAAATGCCCTCTTC -3′.…”

Section: Exome and Sanger Sequencingmentioning

confidence: 99%

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

et al. 2015

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The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.

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Homozygous missense mutation inMED25segregates with syndromic intellectual disability in a large consanguineous family

Abstract: These findings demonstrate that the combination of field investigation of families in highly inbred regions with modern technologies is an effective way for identifying new genes associated with ID.

Cited by 26 publications

References 37 publications

COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants

COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants

Homozygous MED25 mutation implicated in eye–intellectual disability syndrome

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

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