10‐year‐old female with intragenic <i>KANSL1</i> mutation, no <i>KANSL1</i>‐related intellectual disability, and preserved verbal intelligence

Keen, Colleen; Samango‐Sprouse, Carole; Dubbs, Holly; Zackai, Elaine H.

doi:10.1002/ajmg.a.38080

Cited by 4 publications

(2 citation statements)

References 11 publications

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“…All patients that were included in this study present the full spectrum of KdVS associated symptoms. KdVS 1 [ 19 ] and KdVS 2 [ 17 , 86 ] originate from two individual, female KdVS patients with mutations in KANSL1, while the iPSC line KdVS 3 originates from a female patient with a 17q microdeletion [ 19 , 87 ]. We used one independent female control lines (C 2 ).…”

Section: Methodsmentioning

confidence: 99%

Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders

et al. 2021

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Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species-and MTOR-dependent autophagy.

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Section: Methodsmentioning

confidence: 99%

Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders

et al. 2021

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“…Cleft palate and hearing loss (conductive or sensorineural) may also occur, but are less common [6,7]. Communication deficits have also been observed as part of the complex profile seen in KdVS [6,8,9]. Based on a limited number of case reports, expressive communication is suggested to be severely impaired in the preschool years, characterised by a striking late onset of first words (as late as 3 years of age) and a need for therapy in both verbal and nonverbal domains (e.g., sign language, aided communication, such as computer touch screens) [5,6,8,10].…”

Section: Introductionmentioning

confidence: 99%

Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia

et al. 2017

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Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0-27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5-3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding 'double hit' of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development.

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Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report

Zhang,

Yuan,

Fan

et al. 2024

Medicine

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Rationale: Koolen-De Vries syndrome (KdVS, OMIM: 612452), also known as 17q21.31 microdeletion syndrome, is an autosomal dominant genetic disease. In the study, we analyze of clinical phenotype and gene variation of a child with Koolen-De Vries syndrome, review the literature to improve the understanding of the disease. Patient concerns: The patient is a male, aged 1 month and 3 days. The patient has poor airway development, difficulty weaning from respiratory support, seizures, and recurrent low granulocyte counts. Diagnoses: High-throughput sequencing showed a heterozygous mutation NM_001193466.1: c.1574_1578del (P.525HFS *24) in the KANSL1 gene of the proband, which was considered a new mutation since neither of his parents carried this mutation based on Sanger sequencing results. Combining clinical features and genetic results, the proband was diagnosed as KdVS. Interventions and outcomes: The patient was in good condition after receiving bronchoscopy and laser interventional therapy, meeting the criteria for discharge. Follow-up for 1 year and 6 months indicated that the patient’s physical signs were normal and there was no recurrence. Lessons: According to literature review, KdVS is a multi-organ disease characterized by feeding difficulties, seizures, characteristic facial features, dysplasia of the respiratory system and cardiac abnormalities. In this study, laryngeal malacia accounted for 23.2% of the clinical manifestations of KdVS patients, limb convulsions/seizures accounted for 62.5%, and cardiac development defects accounted for 23.5%. The disease was rare in China and had a variety of clinical manifestations. The summary of reported cases can enable doctors to have more understanding of the disease. The new mutations enrich the KANSL1 gene mutation spectrum.

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10‐year‐old female with intragenic KANSL1 mutation, no KANSL1‐related intellectual disability, and preserved verbal intelligence

Cited by 4 publications

References 11 publications

Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders

Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders

Early speech development in Koolen de Vries syndrome limited by oral praxis and hypotonia

Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report

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