Wiedemann-Steiner Syndrome as a Differential Diagnosis of Cornelia de Lange Syndrome Using Targeted Next-Generation Sequencing: A Case Report

Demir, Selma; Gürkan, Hakan; Öz, Veysel; Yalçıntepe, Sinem; Atlı, Emine İkbal

doi:10.1159/000511971

Cited by 11 publications

(12 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the combination of ptosis and long eyelashes was more frequent in KMT2A patients than NIPBL patients (24). Four of these six patients (two patients in our study and two patients in literature) had features of ptosis and hypertelorism, which may help to distinguish WDSTS and CdLS (13,16).…”

Section: Discussionmentioning

confidence: 51%

“…In this study, we analyzed six patients with features of CdLS, and identified six variants in five non-cohesion genes. To date, 40 sporadic patients with features of CdLS caused by non-cohesion variants had been reported (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). We also evaluated the clinical features of these patients, and calculate the clinical scores of these patients according to the 2018 consensus statement to assess the reliability of 11-points scale criteria in the diagnosis of CdLS.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Shangguan

Chen

2022

Front. Pediatr.

View full text Add to dashboard Cite

BackgroundCornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS.ObjectivesThis study describes six variants of non-cohesion genes (KDM6A, KMT2D, KMT2A ANKRD11, and UBE2A), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS.MethodsWhole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with NIPBL variants were summarized. Clinical score comparison among patients with NIPBL variants versus those with variants in non-cohesin genes was performed.ResultsVariants in non-cohesion genes were found in six patients [KMT2A (n = 2), KMT2D, ANKRD11, KDM6A, and UBE2A]. Of them, four variants (KMT2A c.7789C > T, ANKRD11 c.1757_1776del, KDM6A c.655-1G > A, and UBE2A c.439C > T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in ANKRD11 cohort, SETD5 cohort, and AFF4 cohort was statistically lower than those in NIPBL cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; p < 0.05). The average clinical score of KMT2A cohort, EP300 cohort, and NIPBL cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; p > 0.05).ConclusionWe described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (KMT2D, KDM6A, and UBE2A) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.

show abstract

Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Shangguan

Chen

2022

Front. Pediatr.

View full text Add to dashboard Cite

show abstract

“…Similarly, cryptorchidism, not reported in patients with SBDS mutations (PubMed and Google Scholar search, June 2022, using cryptorchidism AND Shwachman-Diamond Syndrome), is present in UPN 43, its prevalence in the normal population is 1.7%, and observed in about 20–35% of WDSTS cases [ 49 , 61 , 62 ]. However, despite the fact that cryptorchidism has been reported in some WDSTS patients, it has never been associated with KMT2A mutations; instead, it has been associated with TASP1, which is a regulator of KMT2A [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

Taha

Paoli²,

Foroni

et al. 2022

Genes

View full text Add to dashboard Cite

Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G>A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

show abstract

“…As a matter of fact, CdLS is now considered a “clinical spectrum” rather than an isolated syndrome with unique features ( Selicorni et al, 2021 ). Genes found mutated in patients with an initial diagnosis of CdLS are: EP300 (( Aoi et al, 2019 ) - Patient 6; ( Cucco et al, 2020 ); - Patient A; ( Squeo et al, 2020 ); - GDB1418; ( Woods et al, 2014 ); - Case Report)), KMT2A (( Yuan et al, 2015 ) - CdLS-3 (BAB4964); ( Parenti et al, 2017 ); - Patient 12; ( Aoi et al, 2019 ); - Patient 27; ( Demir et al, 2021 ); - Case Report)); TAF1 (( O’Rawe et al, 2015 ) - Individual 4A; ( Cheng et al, 2020 ); - Individual 13) causative of Mental Retardation X-Linked Syndromic 33 (MRXS33, OMIM # 300966 )); ZMYND11(( Aoi et al, 2019 ) - Patient 53) causative of Mental Retardation Autosomal Dominant 30 (MRD30, OMIM # 616083 )); PHIP (( Aoi et al, 2019 ) - Patient 56) associated to Developmental Delay Intellectual Disability Obesity and Dysmorphism or Chung-Jansen syndrome (CHUJANS, OMIM # 617991 )), CREBBP (( Tang et al, 2019 ) - Patient 3)); SETD5 (( Squeo et al, 2020 ) - GDB1400) causative of MRD23). These genes, involved in chromatin regulation, are associated with syndromes different from CdLS, but studies conducted exploiting animal models highlighted some similar characteristics that can be found in the human patients affected with CdLS.…”

Section: Animal Models For Chromatinopathiesmentioning

confidence: 99%

Epigenetic disorders: Lessons from the animals–animal models in chromatinopathies

Fede

Grazioli

Lettieri

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Chromatinopathies are defined as genetic disorders caused by mutations in genes coding for protein involved in the chromatin state balance. So far 82 human conditions have been described belonging to this group of congenital disorders, sharing some molecular features and clinical signs. For almost all of these conditions, no specific treatment is available. For better understanding the molecular cascade caused by chromatin imbalance and for envisaging possible therapeutic strategies it is fundamental to combine clinical and basic research studies. To this end, animal modelling systems represent an invaluable tool to study chromatinopathies. In this review, we focused on available data in the literature of animal models mimicking the human genetic conditions. Importantly, affected organs and abnormalities are shared in the different animal models and most of these abnormalities are reported as clinical manifestation, underlying the parallelism between clinics and translational research.

show abstract

Wiedemann-Steiner Syndrome as a Differential Diagnosis of Cornelia de Lange Syndrome Using Targeted Next-Generation Sequencing: A Case Report

Cited by 11 publications

References 25 publications

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Phenotypes of Cornelia de Lange syndrome caused by non-cohesion genes: Novel variants and literature review

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

Epigenetic disorders: Lessons from the animals–animal models in chromatinopathies

Contact Info

Product

Resources

About