Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS

Masciadri, Maura; Ficcadenti, Anna; Milani, Donatella; Cogliati, Francesca; Divizia, Maria Teresa; Larizza, Lidia; Russo, Silvia

doi:10.3389/fneur.2018.00967

Cited by 5 publications

(4 citation statements)

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“…Splice variants appear to occur more often in patients with a more severe phenotype (22). Nonetheless, few family cases with splice variants and mild phenotype have been reported (23). However, based on our data, such variants in a mosaic stage can also be detected in CdLS patients with a mild phenotype.…”

Section: Discussionmentioning

confidence: 99%

Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

2019

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Background: Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex. Methods: Sixty-nine patients with confirmed clinical diagnosis of CdLS were enrolled in the study. Blood and buccal swab samples were collected for molecular studies. Mutational analysis was performed using the Next Generation (deep) Sequencing (NGS) covering 24 genes. In addition, the MLPA technique was applied to detect large rearrangements of NIPBL . Results: MLPA and NGS analysis were performed in 66 (95,7%) and 67 (97,1%) patients, respectively. Large rearrangements of NIPBL were not identified in the studied group. Germline pathogenic variants were detected in 18 (26,1%) patients. Fourteen variants (20,3%) were identified in NIPBL , two (2,9%) in SMC1A , and two (2,9%) in HDAC8 . In total, 13 (18,8%) buccal swabs were suitable for deep sequencing. Mosaic variants were found in four (30,8%; 4/13) patients negative for germline alterations. Three mosaic substitutions were detected in NIPBL while one in KMT2A gene. Conclusions: Comprehensive and sensitive molecular techniques allow detecting novel pathogenic variants responsible for the molecular basis of CdLS. In addition, molecular testing of different tissues should be applied since such an approach allows detect mosaic variants specific for a subgroup of CdLS patients. Finally, to test possible pathogenicity of intronic variants, RNA analysis should be conducted.

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Section: Discussionmentioning

confidence: 99%

Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

2019

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“… Comparison of typical facial features of ( A ) Wiedemann–Steiner syndrome [ 26 ]; ( B ) Coffin–Siris syndrome; ( C ) Kabuki syndrome; ( D ) Cornelia De Lange syndrome [ 27 ]; ( E ) Rubinstein–Taybi syndrome [ 28 ]. …”

Section: Figurementioning

confidence: 99%

KMT2A: Umbrella Gene for Multiple Diseases

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Bernardelli

et al. 2022

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KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann–Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

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“…This approach could be especially relevant regarding CdLS. In this disorder, although a number of familial cases have been reported ( Gillis et al, 2004 ; Krantz et al, 2004 ; Slavin et al, 2012 ), only exceptionally, the presence of the causative variant could be confirmed in blood-derived DNA of the parents ( Niu et al, 2006 ; Deardorff et al, 2007 ; Slavin et al, 2012 ; Krawczynska et al, 2018 ; Masciadri et al, 2018 ). The reason could fairly lie either in the lack of sensitiveness of the detection method or in the presence of the variant strictly in some germinal cells.…”

Section: Introductionmentioning

confidence: 96%

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome

et al. 2022

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Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.

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Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS

Cited by 5 publications

References 15 publications

Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

KMT2A: Umbrella Gene for Multiple Diseases

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome

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