Investigation of modifier genes within copy number variations in Rett syndrome

Artuso, Rosangela; Papa, Filomena Tiziana; Grillo, Elisa; Mucciolo, Mafalda; Yasui, Dag H.; Dunaway, Keith W.; Disciglio, Vittoria; Mencarelli, Maria Antonietta; Pollazzon, Marzia; Zappella, Michele; Hayek, Joussef; Mari, Francesca; Renieri, Alessandra; LaSalle, Janine M.; Ariani, Francesca

doi:10.1038/jhg.2011.50

Cited by 28 publications

(22 citation statements)

References 65 publications

(66 reference statements)

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“…[5] This gene product localizes to cell-substrate adhesion sites and sites of dynamic actin assembly and disassembly participating in axonal outgrowth, dendrite morphology, synapse formation, and axon guidance. Although ENAH mutations are not listed in Tables S1–S3 in File S1, classical RTT patient #138 had a 4bp insertion (insAAAC) in the UTR3 region of the ENAH gene (position 225,675,743), at a site that is predicted to be conserved (Phylo P = 0.52) (the entire list of mutations is available on request).…”

Section: Discussionmentioning

confidence: 99%

“…[4] However, in the current study each pair of sisters had the same MECP2 mutation and XCI. [5] Thus, these two pairs of sisters represent an ideal model to test additional factors that modulate the expression variability.…”

Section: Discussionmentioning

confidence: 99%

“…[4] However, all four mentioned individuals have a balanced XCI, indicating that other factors beyond XCI may contribute to the phenotypic outcome. [3], [5], [6] Thus, these pairs of sisters represent the ideal model to test the molecular basis of expression variability using an exome sequencing approach.…”

Section: Introductionmentioning

confidence: 99%

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Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

et al. 2013

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Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

et al. 2013

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“…In the female Patient 1 with autism, the additional 1.11-Mb duplication CNV of 10q11.2 overlaps multiple CNVs in the DGV but also contains a minimum of 9 genes. Of these, duplication of the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene is a candidate modifier of severity in Rett syndrome 29 and might conceivably interact with other candidate autism genes in 16p11.2-p12.2 duplications. In the male Patient 2 without autism, an additional duplication CNV of 1.52 Mb in Xp22.31 contains a minimum of 5 genes, including the steroid sulfatase (STS) gene, but there is growing evidence that duplication CNVs containing STS are benign population variants.…”

Section: Modifiers or Second Hitsmentioning

confidence: 99%

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

et al. 2012

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Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.

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“…MRPA, which is the most severely affected, besides the IMMP2L deletion, has a 2Mb de novo duplication at 10q11.22. This alteration overlaps multiple CNVs described in DGV but has also been found in patients with intellectual disability and language impairment, milder Zapella variant and autism (ARTUSO et al, 2011;CHILIAN et al, 2013;BARBER et al, 2013). An interesting gene within this duplicated region, is GPRIN2.…”

Section: Discussionsupporting

confidence: 64%

Estudo de genes candidatos aos Transtornos do Espectro Autista

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Investigation of modifier genes within copy number variations in Rett syndrome

Cited by 28 publications

References 65 publications

Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

Estudo de genes candidatos aos Transtornos do Espectro Autista

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