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Novel MED12 variant in a multiplex Fragile X syndrome family: dual molecular etiology of two X-linked intellectual disabilities with autism in the same family
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In: ISSN: 0301-4851 ; EISSN: 1573-4978 ; Molecular Biology Reports ; https://hal-riip.archives-ouvertes.fr/pasteur-03565723 ; Molecular Biology Reports, Springer Verlag, 2019, 46 (4), pp.4185 - 4193. ⟨10.1007/s11033-019-04869-6⟩ (2019)
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Abstract:
International audience ; Studies of X-linked pedigrees were the first to identify genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD). However, some pedigrees present a huge clinical variability between the affected members. This intrafamilial heterogeneity may be due to cooccurrence of two disorders. In the present study, we describe a multiplex X-linked pedigree in which three siblings have ID, ASD and dysmorphic features but with variable severity. Through Fragile X syndrome test, we identified the full FMR1 mutation in only two males. Whole exome sequencing allowed us to identify a novel hemizygous variant (p.Gln2080_Gln2083del) in MED12 gene in two males. So, the first patient has FXS, the second has both FMR1 and MED12 mutations while the third has only the MED12 variant. MED12 mutations are implicated in several forms of X-linked ID. Family segregation and genotype-phenotype-correlation were in favor of a cooccurrence of two forms of X-linked ID. Our work provides further evidence of the involvement of MED12 in XLID. Moreover, through these results, it is noteworthy to raise awareness that intrafamilial heterogeneity in FXS multiplex families could result from the cooccurrence of multiple clinical entities involving at least two separate genetic loci. This should be taken into consideration for genetic testing and counselling in patients/families with atypical disease symptoms.
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Keyword:
[SDV]Life Sciences [q-bio]; Autism spectrum disorder; Dual diagnosis; FMR1; Fragile X syndrome; Intellectual disability; MED12; MESH: Adolescent; MESH: Autistic Disorder; MESH: Family; MESH: Fragile X Mental Retardation Protein; MESH: Fragile X Syndrome; MESH: Genes; MESH: Genetic Association Studies; MESH: Genetic Variation; MESH: Humans; MESH: Intellectual Disability; MESH: Male; MESH: Mediator Complex; MESH: Mutation; MESH: Pedigree; MESH: Phenotype; MESH: Siblings; MESH: Whole Exome Sequencing; X-Linked
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URL: https://doi.org/10.1007/s11033-019-04869-6
https://hal-riip.archives-ouvertes.fr/pasteur-03565723
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| 2 |
Metformin treatment in young children with fragile X syndrome.
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In: Molecular genetics & genomic medicine, vol 7, iss 11 (2019)
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A Pilot Quantitative Evaluation of Early Life Language Development in Fragile X Syndrome
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In: Brain Sciences ; Volume 9 ; Issue 2 (2019)
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DDX3X and specific initiation factors modulate FMR1 repeat‐associated non‐AUG‐initiated translation
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Trastornos del habla en el síndrome X frágil. Una revisión bibliográfica ; Speech disorders in fragile X syndrome. A bibliographical review
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