DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation

Guerra, João Victor da Silva; Oliveira-Santos, José; Oliveira, Danyllo; Leal, Gabriela Ferraz; Oliveira, João Ricardo Mendes de; Costa, Silvia Souza da; Krepischi, Ana Cristina Victorino; Vianna‐Morgante, Angela Maria; Maschietto, Mariana

doi:10.1016/j.ejmg.2019.103737

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…[1][2][3][4][5][6] Specific patterns in the methylomes of individuals with defined congenital syndromes have recently received particular attention in clinical settings. [7][8][9] The elucidation of DNA methylation patterns in a range of constitutional syndromes has led to the recognition that these episignatures represent an early event during embryo development, and thus are present in numerous tissues of the affected individuals, including peripheral blood, the most common source of DNA specimens in diagnostic laboratories. 10,11 The stability of DNA methylation patterns provides ground for their use in clinical diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Aref‐Eshghi

Kerkhof

Pedro

et al. 2020

The American Journal of Human Genetics

197

242

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Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called ''episignatures''). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

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Section: Introductionmentioning

confidence: 99%

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Aref‐Eshghi

Kerkhof

Pedro

et al. 2020

The American Journal of Human Genetics

197

242

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“…To date, 57 pathogenic variations on the KDM5C gene have been described in the English literature. 9,14,15,18,[25][26][27][28][29][30][31][32][33][34][35][36] We summarized their loci and clinical manifestations in Figure 5. Of interest, the missense and splice site variations commonly occur in functional domains, and the nonsense and frameshift variations are frequently in nonfunctional regions.…”

Section: Discussionmentioning

confidence: 99%

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

Chiang

et al. 2022

Neurol Genet

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Background and ObjectivesTo investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature.MethodsPhysical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells.ResultsWe identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C.DiscussionWe report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.

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“…KDM5C is involved in 0.7% to 2.8% of XLID, with 35 reported disease‐causing variants including missense, nonsense and frameshift variants in humans 2,10‐24 …”

Section: Introductionmentioning

confidence: 99%

“…9 KDM5C is involved in 0.7% to 2.8% of XLID, with 35 reported disease-causing variants including missense, nonsense and frameshift variants in humans. 2,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] The main molecular mechanism underlying KDM5C-linked XLID appears to be loss of enzymatic function. 4,6,15,21 Males with KDM5C variants usually present with moderate to severe ID, with language impairment, behavioral disorders, epilepsy, distinctive facial features (small forehead, prognathism, micrognathia, maxillary hypoplasia, facial hypotonia and flat philtrum), short stature, or microcephaly (MIM #300534).…”

mentioning

confidence: 99%

“…4,6,15,21 Males with KDM5C variants usually present with moderate to severe ID, with language impairment, behavioral disorders, epilepsy, distinctive facial features (small forehead, prognathism, micrognathia, maxillary hypoplasia, facial hypotonia and flat philtrum), short stature, or microcephaly (MIM #300534). 2,10,13 Most of the variants are maternally inherited (48/50 reported heterozygous carriers) 2,10,[12][13][14][15][16][17][18][20][21][22][23]25 from usually asymptomatic or mildly affected females. Some articles reported affected women with learning disabilities or moderate ID, short stature, and mild facial particularities such as deep-set eyes and high broad nasal bridge, however, without providing precise clinical descriptions.…”

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confidence: 99%

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Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

et al. 2020

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X‐linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.

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DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation

Cited by 10 publications

References 28 publications

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

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