X‐linked intellectual disability related genes disrupted by balanced X‐autosome translocations

Moysés-Oliveira, Mariana; Guilherme, Roberta Santos; Meloni, Vera Ayres; Di-Battista, Adriana; Mello, Cláudia Berlim de; Bragagnolo, Silvia; Moretti-Ferreira, Danilo; Kosyakova, Nadezda; Liehr, Thomas; Carvalheira, Gianna; Melaragno, Maria Isabel

doi:10.1002/ajmg.b.32355

Cited by 34 publications

(33 citation statements)

References 37 publications

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“…Of these, seven reported patients with sequence alterations of KIAA2022 or structural X-chromosome abnormalities affecting KIAA2022, 1–3 5 9–11 whereas the other six did not describe patients. In these first seven publications, 15 male patients were described.…”

Section: Resultsmentioning

confidence: 99%

“…Five affected males from one family5 are excluded from the table, because only limited clinical data were available. Three female patients affected by KIAA2022 disruptions have previously been reported,9–11 two with a phenotype comparable with that in males, and one with mild ID. Clinical characteristics are given in tables 1 and 3.…”

Section: Resultsmentioning

confidence: 99%

“…Moyses-Oliveira et al reported a female patient with a balanced X-autosomal translocation disrupting KIAA2022 at intron 1 9. XCI studies showed inactivation of the normal X-chromosome in all cells, leading to complete absence of KIAA2022 expression.…”

Section: Discussionmentioning

confidence: 99%

“…2 5 Nevertheless, a few affected female patients have recently been described 9–11. Here, we report 14 female patients with heterozygous de novo mutations of KIAA2022 .…”

Section: Introductionmentioning

confidence: 92%

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De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

et al. 2016

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BackgroundMutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy.MethodsReported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible.ResultsAll mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles.ConclusionsHeterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…2 5 Nevertheless, a few affected female patients have recently been described 9–11. Here, we report 14 female patients with heterozygous de novo mutations of KIAA2022 .…”

Section: Introductionmentioning

confidence: 92%

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De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

et al. 2016

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“…S7). In humans, numerous abnormal phenotypes, including intellectual disability and congenital anomalies, are caused by gene disruptions resulting from balanced rearrangements (Fruhmesser et al 2013;Schluth-Bolard et al 2013;Moyses-Oliveira et al 2015;Schneider et al 2015). This would occur in 6% of de novo reciprocal translocations and 9% of de novo inversions, but these events are detrimental and therefore remain rare in the population.…”

Section: Discussionmentioning

confidence: 99%

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

et al. 2016

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Reconstructing genome history is complex but necessary to reveal quantitative principles governing genome evolution. Such reconstruction requires recapitulating into a single evolutionary framework the evolution of genome architecture and gene repertoire. Here, we reconstructed the genome history of the genus Lachancea that appeared to cover a continuous evolutionary range from closely related to more diverged yeast species. Our approach integrated the generation of a high-quality genome data set; the development of AnChro, a new algorithm for reconstructing ancestral genome architecture; and a comprehensive analysis of gene repertoire evolution. We found that the ancestral genome of the genus Lachancea contained eight chromosomes and about 5173 protein-coding genes. Moreover, we characterized 24 horizontal gene transfers and 159 putative gene creation events that punctuated species diversification. We retraced all chromosomal rearrangements, including gene losses, gene duplications, chromosomal inversions and translocations at single gene resolution. Gene duplications outnumbered losses and balanced rearrangements with 1503, 929, and 423 events, respectively. Gene content variations between extant species are mainly driven by differential gene losses, while gene duplications remained globally constant in all lineages. Remarkably, we discovered that balanced chromosomal rearrangements could be responsible for up to 14% of all gene losses by disrupting genes at their breakpoints. Finally, we found that nonsynonymous substitutions reached fixation at a coordinated pace with chromosomal inversions, translocations, and duplications, but not deletions. Overall, we provide a granular view of genome evolution within an entire eukaryotic genus, linking gene content, chromosome rearrangements, and protein divergence into a single evolutionary framework.

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Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability

et al. 2017

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IMPORTANCECopy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability.OBJECTIVES To evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability. DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures.MAIN OUTCOMES AND MEASURES DNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient's phenotype. RESULTSOf the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty-three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation: ABAT, KIAA2022, COL4A1, CACNA1C, and SMARCA2. ABAT duplication was associated with Lennox-Gastaut syndrome and KIAA2022 deletion with Jeavons syndrome. CONCLUSIONS AND RELEVANCEThe high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes.

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X‐linked intellectual disability related genes disrupted by balanced X‐autosome translocations

Cited by 34 publications

References 37 publications

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

Reconstruction of ancestral chromosome architecture and gene repertoire reveals principles of genome evolution in a model yeast genus

Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability

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