Cohesin complex-associated holoprosencephaly

Kruszka, Paul; Berger, Seth; Casa, Valentina; Dekker, Mike R.; Gaesser, Jenna; Weiss, Karin; Martinez, Ariel F.; Murdock, David R.; Louie, Raymond J.; Prijoles, Eloise J.; Lichty, Angie; Brouwer, Oebele F.; Zonneveld‐Huijssoon, Evelien; Stephan, Mark J.; Hogue, Jacob S.; Hu, Ping; Tanima-Nagai, Momoko; Everson, Joshua L.; Prasad, Chitra; Cereda, Anna; Iascone, Maria; Schreiber, Allison; Zurcher, Vickie; Corsten‐Janssen, Nicole; Escobar, Luis; Clegg, Nancy J.; Delgado, Mauricio R.; Hajirnis, Omkar; Balasubramanian, Meena; Kayserili, Hülya; Deardorff, Matthew A.; Poot, Raymond A.; Wendt, Kerstin S.; Lipinski, Robert J.; Muenke, Maximilian

doi:10.1093/brain/awz210

Cited by 48 publications

(56 citation statements)

References 60 publications

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“…We describe in Table S6 SMC1A 2 / 1 G A T S 3 C M S 1 3 6 8 2 6 8 5 5 3 0 4 2 6 3 3 0 1 Table S6). b Genomic region showing the microdeletions including RAD21 with involvement of other morbid genes (Deardorff et al 2012;Maas et al 2015;Pereza et al 2012;Wuyts et al 2002;Yuen et al 2015), variants reported as variant of unknown significance (VUS) that remained with unknown significance subsequent to re-evaluation, and cases for whom the relationship between phenotype and RAD21 variant could not be confirmed (Kruszka et al 2019;Zhang et al 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Of the 49 cases, 24 are new. Twentyfive were previously published (Ansari et al 2014;Bonora et al 2015;Boyle et al 2017;Deardorff et al 2012;Dorval et al 2019;Gudmundsson et al 2018;Kruszka et al 2019;Lee et al 2014;Martinez et al 2017;McBrien et al 2008;Minor et al 2014;Yuan et al 2019), and for 19 of these clinical data could be updated (Table 1). Patients originated from Australia, Belgium, Canada, Denmark, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, Turkey, United Kingdom and United States.…”

Section: Resultsmentioning

confidence: 99%

“…RAD21 variants have also been associated with sclerocornea (Zhang et al 2019) and Mungan syndrome (Chronic Idiopatic Intestinal Pseudoobstruction; OMIM #611376, in patients with biallelic RAD21 variants) (Bonora et al 2015;Mungan et al 2003), each in a single family in which no remarks on CdLS features were made in the report. Loss of function-variants in cohesin genes including RAD21 were found in individuals with holoprosencephaly of whom some demonstrated CdLS features as well (Kruszka et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.Zeynep Tümer and Raoul C. Hennekam contributed equally.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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“…Genetic causes of non‐syndromic holoprosencephaly involve mutations in genes involved in the SHH pathway, the most common of which are SSH , SIX3 , and ZIC2 (Kruszka, Martinez, & Muenke, ). Recently, it was also described that mutations in the chromatid cohesion complex may also cause non‐syndromic holoprosencephaly (Kruszka et al, ). These etiologies of holoprosencephaly do not currently explain the holoprosencephaly phenotype in our patient.…”

Section: Discussionmentioning

confidence: 99%

Holoprosencephaly in Kabuki syndrome

Daly

Roberts

Yang

et al. 2019

American J of Med Genetics Pt A

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Kabuki syndrome is a rare, multi‐systemic disorder of chromatin regulation due to mutations in either KMT2D or KDM6A that encode a H3K4 methyltransferase and an H3K27 demethylase, respectively. The associated clinical phenotype is a direct result of temporal and spatial changes in gene expression in various tissues including the brain. Although mild to moderate intellectual disability is frequently recognized in individuals with Kabuki syndrome, the identification of brain anomalies, mostly involving the hippocampus and related structures remains an exception. Recently, the first two cases with alobar holoprosencephaly and mutations in KMT2D have been reported in the medical literature. We identified a de novo, pathogenic KMT2D variant (c.6295C > T; p.R2099X) using trio whole‐exome sequencing in a 2‐year‐old female with lobar holoprosencephaly, microcephaly and cranio‐facial features of Kabuki syndrome. This report expands the spectrum of brain anomalies associated with Kabuki syndrome underscoring the important role of histone modification for early brain development.

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“…Importantly, and to our knowledge, only one previous case report of HPE patient with SIX3 variant and CHD is documented in the literature (Poelmans et al, ). In a recent study, we showed that in six patients with HPE and loss of function variant in STAG2 , four (67%) had structural heart anomalies, and furthermore, 58% (7/12) of all reported loss of function variants in STAG2 in the medical literature are associated with structural heart defects (Aoi et al, ; Kruszka et al, ). Interestingly, in the present study, none of the 37 individuals with HPE and ZIC2 variants had CHD, contrasting with previous reports of a 9% incidence of CHD in 157 patients with ZIC2 variants (Solomon et al, ) and a 14% incidence of CHD in 53 patients with ZIC2 variants (Mercier et al, ).…”

Section: Discussionmentioning

confidence: 93%

Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene‐specific

Tekendo‐Ngongang

Owosela

Muenke

et al. 2020

American J of Med Genetics Pt C

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Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE‐related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left–right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE‐affected individuals with or without identifiable genetic variants, and this co‐occurrence may be genetically driven and gene‐specific.

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Cohesin complex-associated holoprosencephaly

Cited by 48 publications

References 60 publications

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Holoprosencephaly in Kabuki syndrome

Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene‐specific

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