The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Rots, Dmitrijs; Jakub, Taryn E.; Keung, Crystal; Jackson, Adam; Banka, Siddharth; Pfundt, Rolph; Vries, Bert B.A. de; Jaarsveld, Richard H. van; Hopman, Saskia; Binsbergen, Ellen van; Valenzuela, Irene; Hempel, Maja; Bierhals, Tatjana; Kortüm, Fanny; Lecoquierre, François; Goldenberg, Alice; Hertz, Jens Michael; Andersen, Charlotte Brasch; Kibæk, Maria; Prijoles, Eloise J.; Stevenson, Roger E.; Everman, David B.; Patterson, Wesley G.; Meng, Linyan; Gijavanekar, Charul; Dios, Karl De; Lakhani, Shenela; Levy, Tess; Wagner, Matias; Wieczorek, Dagmar; Benke, Paul J.; García, Marta; Perrier, Renee; Sousa, Sérgio B.; Almeida, Pedro; Simões, Maria José; Isidor, Bertrand; Deb, Wallid; Schmanski, Andrew A.; Abdul‐Rahman, Omar; Philippe, Christophe; Bruel, Ange‐Line; Faivre, Laurence; Vitobello, Antonio; Thauvin, Christel; Smits, Jeroen J.; Garavelli, Livia; Caraffi, Stefano Giuseppe; Peluso, Francesca; Davis‐Keppen, Laura; Platt, Dylan; Royer, Erin; Leeuwen, Lisette; Sinnema, Margje; Stegmann, Alexander P.A.; Stumpel, Constance T. R. M.; Tiller, George E.; Bosch, Daniëlle G.M.; Potgieter, Stephanus T.; Joss, Shelagh; Splitt, Miranda; Holden, Simon; Prapa, Matina; Foulds, Nicola; Douzgou, Sofia; Puura, Kaija; Waltes, Regina; Chiocchetti, Andreas G.; Freitag, Christine M.; Satterstrom, F. Kyle; Rubeis, Silvia De; Buxbaum, Joseph D.; Gelb, Bruce D.; Aleksić, Branko; Kushima, Itaru; Howe, Jennifer; Scherer, Stephen W.; Arado, Alessia; Baldo, Chiara; Patat, Olivier; Bénédicte, Demeer; Lopergolo, Diego; Santorelli, Filippo M.; Haack, Tobias B.; Dufke, Andreas; Bertrand, Miriam; Falb, Ruth; Rieß, Angelika; Krieg, Peter; Spranger, Stephanie; Bedeschi, Maria Francesca; Iascone, Maria; Josephi-Taylor, Sarah; Roscioli, Tony; Buckley, Michael F.; Liebelt, Jan; Dagli, Aditi I; Aten, Emmelien; Hurst, Anna; Hicks, Alesha; Suri, Mohnish; Aliu, Ermal; Naik, Sunil G.; Sidlow, Richard; Coursimault, Juliette; Nicolas, Gaël; Küpper, Hanna; Petit, Florence; Ibrahim, Veyan; Top, Deniz; Cara, Francesca Di; Louie, Raymond J.; Stolerman, Elliot; Brunner, Han G.; Vissers, Lisenka E.L.M.; Kramer, Jamie M.; Kleefstra, Tjitske

doi:10.1016/j.ajhg.2023.04.008

Cited by 4 publications

(12 citation statements)

References 65 publications

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“…In line with the reported KDM6B phenotype, our patient presented with mild motor delay, but he didn't show language impairment or intellectual disability (ID), common clinical presentations of the disease. He also showed ligamentous laxity, hypotonia, ASD, and ADHD traits, reported in about half of the patients (Insa Pineda & G omez González, 2022; Rots et al, 2023;Stolerman et al, 2019). In addition, our patient's medical history was positive for gastroesophageal reflux disease and a single episode of generalized-onset seizure, findings already described in a small subset of patients(5).…”

Section: Discussionsupporting

confidence: 67%

“…"Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities" caused by heterozygous pathogenic variants in KDM6B, is a recently described syndrome characterized by a set of clinical features such as gastroesophageal reflux disease, non-specific facial dysmorphisms, ligamentous laxity, hypotonia, language delay, motor delay, cognitive impairment, sleeping problems. ADHD and ADHD traits, autism spectrum disorder (ASD) and ASD traits, psychosis, epilepsy and behavioral problems are also described (Insa Pineda & G omez González, 2022;Rots et al, 2023;Stolerman et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, our patient's medical history was positive for gastroesophageal reflux disease and a single episode of generalized-onset seizure, findings already described in a small subset of patients(5). Dysgraphia has never been described in association with KDM6B variants, while a specific learning disorder, dyslexia, was already described once in a proband's affected father (Rots et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…years, advances in technologies have led to identify genetic etiologies in up to a half of NDDs (Savatt & Myers, 2021). A rare NDD named "Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities" (OMIM #618505) has been described in 84 patients carrying heterozygous (likely) pathogenic variants in KDM6B, mostly truncating and occurring de novo (Insa Pineda & G omez González, 2022;Rots et al, 2023;Stolerman et al, 2019). KDM6B (Lysine Demethylase 6B), also named JMJD3 or KIAA0346 (MIM *611577), is located on locus 17p13.1 and encodes for the histone H3 lysine 27 (H3K27) demethylase, which plays a key role in gene expression through the regulation of neuronal and non-neuronal commitment and differentiation during development (Kartikasari et al, 2013;Li et al, 2014;Ohtani et al, 2013;Shan et al, 2020;Smith et al, 2014;Wijayatunge et al, 2014Wijayatunge et al, , 2018Yang et al, 2013;Ye et al, 2012).…”

mentioning

confidence: 99%

“…The main associated clinical features are non-specific facial dysmorphisms, ligamentous laxity, hypotonia, and a wide range of NDDs and behavioral problems (Insa Pineda & G omez González, 2022;Rots et al, 2023;Stolerman et al, 2019). Associated neuroradiological findings, when present, consist in non-specific, minor anomalies involving both supratentorial and infratentorial regions (Insa Pineda & G omez González, 2022;Stolerman et al, 2019).…”

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confidence: 99%

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Cerebellar heterotopia in an 11‐year‐old child with KDM6B‐related neurodevelopmental disorder: A case report and review of the literature

Politano,

D'Abrusco,

Pasca

et al. 2024

American J of Med Genetics Pt A

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Heterozygous pathogenic variants in KDM6B have recently been associated to a rare neurodevelopmental disorder referred to as “Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities” and characterized by non‐pathognomonic facial and body dysmorphisms, a wide range of neurodevelopmental and behavioral disorders and nonspecific neuroradiological findings. KDM6B encodes a histone demethylase, expressed in different tissues during development, which regulates gene expression through the modulation of chromatin accessibility by RNA polymerase. We herein describe a 11‐year‐old male patient carrying a novel de novo pathogenic variant in KDM6B exhibiting facial dysmorphisms, dysgraphia, behavioral traits relatable to oppositional defiant, autism spectrum, and attention deficit hyperactivity disorders, a single seizure episode, and a neuroimaging finding of a single cerebellar heterotopic nodule, never described to date in this genetic condition. These findings expand the phenotypic spectrum of this syndrome, highlighting the potential role for KDM6B in cerebellar development and providing valuable insights for genetic counseling.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cerebellar heterotopia in an 11‐year‐old child with KDM6B‐related neurodevelopmental disorder: A case report and review of the literature

Politano,

D'Abrusco,

Pasca

et al. 2024

American J of Med Genetics Pt A

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Neurodevelopmental functions of CHD8: new insights and questions

Basson

2024

Biochemical Society Transactions

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Heterozygous, de novo, loss-of-function variants of the CHD8 gene are associated with a high penetrance of autism and other neurodevelopmental phenotypes. Identifying the neurodevelopmental functions of high-confidence autism risk genes like CHD8 may improve our understanding of the neurodevelopmental mechanisms that underlie autism spectrum disorders. Over the last decade, a complex picture of pleiotropic CHD8 functions and mechanisms of action has emerged. Multiple brain and non-brain cell types and progenitors appear to be affected by CHD8 haploinsufficiency. Behavioural, cellular and synaptic phenotypes are dependent on the nature of the gene mutation and are modified by sex and genetic background. Here, I review some of the CHD8-interacting proteins and molecular mechanisms identified to date, as well as the impacts of CHD8 deficiency on cellular processes relevant to neurodevelopment. I endeavour to highlight some of the critical questions that still require careful and concerted attention over the next decade to bring us closer to the goal of understanding the salient mechanisms whereby CHD8 deficiency causes neurodevelopmental disorders.

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Chromatin regulatorKdm6bis required for the establishment and maintenance of neural stem cells in mouse hippocampus

Gil,

Hong,

et al. 2024

Preprint

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Neural stem cells (NSCs) in the mouse hippocampal dentate gyrus (DG) – a structure important to learning and memory – generate new neurons postnatally and throughout adult life. However, the regulators that enable this lifelong neurogenesis remain incompletely understood. Here we show that the chromatin regulator KDM6B is required for both the establishment and maintenance of NSCs in the mouse DG. Conditional deletion ofKdm6bin embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective.Kdm6b-deletion causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG. Using single cell RNA sequencing (scRNA-seq), we observed thatKdm6b-deletion disrupts the transcriptomic signature of NSC maintenance. Furthermore, deletingKdm6bin adult DG NSCs induces early neuronal differentiation, and the NSC population is not properly maintained. These data illustrate the critical role thatKdm6bplays in adult DG neurogenesis, which may help understand how mutations in this chromatin regulator result in cognitive disorders in human patients.

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The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Cited by 4 publications

References 65 publications

Cerebellar heterotopia in an 11‐year‐old child with KDM6B‐related neurodevelopmental disorder: A case report and review of the literature

Cerebellar heterotopia in an 11‐year‐old child with KDM6B‐related neurodevelopmental disorder: A case report and review of the literature

Neurodevelopmental functions of CHD8: new insights and questions

Chromatin regulatorKdm6bis required for the establishment and maintenance of neural stem cells in mouse hippocampus

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