Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

Chopra, Maya; McEntagart, Meriel; Clayton‐Smith, Jill; Platzer, Konrad; Shukla, Anju; Girisha, Katta M.; Kaur, Anupriya; Kaur, Parneet; Pfundt, Rolph; Veenstra‐Knol, Hermine E.; Mancini, Grazia M.S.; Cappuccio, Gerarda; Brunetti‐Pierri, Nicola; Kortüm, Fanny; Hempel, Maja; Denecke, Jonas; Lehman, Anna; Kleefstra, Tjitske; Stuurman, Kyra E.; Wilke, Martina; Thompson, Michelle L.; Bebin, E. Martina; Bijlsma, Emilia K.; Hoffer, Mariëtte J.V.; Peeters-Scholte, Cacha; Slavotinek, Anne; Weiss, William A.; Yip, Tiffany; Hodoğlugil, Uğur; Whittle, Amy; diMonda, Janette; Neira, Juanita; Yang, Sandra; Kirby, Amelia; Pinz, Hailey; Lechner, Rosan; Sleutels, Frank; Helbig, Ingo; McKeown, Sarah; Helbig, Katherine L.; Willaert, Rebecca; Juusola, Jane; Semotok, Jennifer; Hadonou, Medard; Short, John; Yachelevich, Naomi; Lala, Sajel; Fernández-Jaén, A; Pelayo, Janvier Porta; Klöckner, Chiara; Kamphausen, Susanne; Jamra, Rami Abou; Arélin, Maria; Innes, A. Micheil; Niskakoski, Anni; Amin, Sam; Williams, Maggie; Evans, Julie; Smithson, Sarah; Smedley, Damian; Burca, Anna de; Kini, Usha; Delatycki, Martin B.; Gallacher, Lyndon; Yeung, Alison; Pais, Lynn; Field, Michael; Martin, Ellenore; Charles, Perrine; Courtin, Thomas; Keren, Boris; Iascone, Maria; Cereda, Anna; Poke, Gemma; Abadie, Véronique; Chalouhi, Christel; Parthasarathy, Padmini; Halliday, Benjamin J.; Robertson, Stephen; Lyonnet, Stanislas; Amiel, Jeanne; Gordon, Christopher T

doi:10.1016/j.ajhg.2021.04.007

Cited by 24 publications

(16 citation statements)

References 33 publications

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“…Clinical studies of ANKRD17 have demonstrated that pathogenic variants cause a neurodevelopmental disorder that manifests with a constellation of intellectual disability, multifocal epilepsy, growth restriction, recurrent infections, skeletal anomalies, dysmorphic facial features and ophthalmological abnormalities. 2 Our patient demonstrated clinical characteristics consistent with that reported in ANKRD17-affected patients, including dysmorphic facial features, speech delays, and multifocal epilepsy. Whereas vascular malformations have not been reported to date in human studies, homozygous ANKRD17-deficient mice have been demonstrated to die from severe hemorrhages in the head, pericardial cavities, and ventral trunk, arising because of defects in vascular smooth muscle development.…”

Section: Discussion/conclusionsupporting

confidence: 87%

“… 1 Mutations of this protein are known to cause a spectrum of neurodevelopmental disorders including developmental delay, dysmorphic facial features, epilepsy, growth restriction, recurrent infections, skeletal anomalies, and ophthalmological abnormalities. 2 In ANKRD17-deficient mice studies, severe embryonic developmental impairments and serious hemorrhages were detected which cause lethality in most cases. However, no studies to date report vascular malformations in human patients with pathogenic variants to ANKRD17.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17

Silverstein

Kuwabara

Appavu

2022

Child Neurology Open

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Ankyrin repeat domain 17 (ANKRD17) is postulated to play a role in the integrity of blood vessels and has been reported to be associated with developmental delays, epilepsy, and growth restriction. Whereas ANKRD17-deficient mice have been demonstrated to experience catastrophic hemorrhages, vascular malformations have not been reported in human patients with pathogenic variants to ANKRD17. We report a term male neonate with a heterozygous de novo variant to ANKRD17 (ANKRD17; c6988 C > G, P.[P2330a]) who experienced subarachnoid hemorrhage from a ruptured aneurysm involving the left middle cerebral artery. He experienced acute symptomatic seizures and required clipping of his aneurysm at 35 days of life, later progressing to developing multifocal drug-resistant epilepsy. To our knowledge, this case represents the first report of a cerebrovascular malformation from a patient with ANKRD17. Further work is needed to investigate whether pathogenic variants to ANKRD17 can lead to cerebral aneurysms or other cerebrovascular malformations in children.

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Section: Discussion/conclusionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17

Silverstein

Kuwabara

Appavu

2022

Child Neurology Open

View full text Add to dashboard Cite

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“…Majority of cases represent de novo mutations; however several instances of familial inheritance has been also described. 1,2 Here, we report an additional case of CAGS in a patient with previously unreported heterozygous missense variant in ANKRD17 gene. Detailed description of clinical manifestations and diagnosis are presented.…”

Section: Introductionmentioning

confidence: 81%

A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report

Tinatin,

Kakha,

Mikheil

et al. 2023

SAGE Open Medical Case Reports

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Chopra-Amiel-Gordon syndrome (OMIM: 619504) is an autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, speech delay, epilepsy, dysmorphic craniofacial features, ophthalmological abnormalities, and recurrent infections. It is caused by heterozygous loss-of-function pathogenic variants in the ANKRD17 gene, which codes for an ankyrin repeat-containing protein. Currently, about 35 cases of Chopra-Amiel-Gordon syndrome are described in the medical literature. We report on a 4-year-old female patient with a novel heterozygous variant in the ANKRD17 gene.

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“…Importantly, while reduction in TH mRNA could be the primary cause of decreased TH protein levels upon mask knockdown, additional translational or post-translational mechanisms may be involved considering the pleiotropic role of Mask. Interestingly, haploinsufficiency of the human ortholog of mask (ANKRD17) was recently identified as the cause of a complex neurodevelopmental disorder (Chopra et al 2021). Further investigation of whether ANKRD17 regulates dopamine levels in the mammalian brain and its mechanistic investigation will likely provide a novel angle to study this understudied rare disease and related conditions.…”

Section: Clu and Mask Reduce Brain Dopamine Levels Through Different ...mentioning

confidence: 99%

RNAi-based screen for cuticle pigmentation inDrosophila melanogasterreveals novel regulators of brain dopamine

Deal,

Bei,

Gibson

et al. 2023

Preprint

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The dopaminergic system has been extensively studied for its role in behavior in various animals as well as human neuropsychiatric and neurological diseases. However, we still know little about how dopamine levels are tightly regulated in vivo. In order to identify novel regulators of dopamine levels, we utilized Drosophila melanogaster cuticle pigmentation as a readout, where dopamine is used as a precursor to melanin. First, we measured dopamine from classical mutants of genes that are known to be important for cuticle pigmentation to understand the relationship between dopamine levels and cuticle color. We then performed an RNAi-based screen to identify novel regulators of cuticle pigmentation. We identified 153 genes that were not only enriched for conserved homologs and disease-associated genes, but were unexpectedly enriched for multiple developmental signaling pathways and mitochondria-associated proteins. Upon measuring dopamine from 35 prioritized candidates from this cohort, we found 10 that caused significant reduction in dopamine in the head while one caused an increase. While most of these 11 genes are expressed in the fly brain, only two of them, clu and mask, altered dopamine levels specifically in the brain upon knockdown in dopaminergic cells. Interestingly, mask may act as a hub of dopamine regulation since it is associated with three nodes found in our screen (Receptor tyrosine kinase/EGF signaling, Hippo signaling, and mitochondrial dynamics). Further examination suggests that Mask likely acts on dopamine synthesis by regulating transcription of the rate-limiting dopamine synthesis enzyme, tyrosine hydroxylase. In conclusion, this screen identified 11 new regulators of dopamine levels and provides molecular handles to investigate how dopamine levels are controlled in vivo, as well as revealed an unexpected relationship between fly pigmentation genes, developmental signaling and human neurological and neurodevelopmental disease genes.

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Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

Cited by 24 publications

References 33 publications

Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17

Neonatal Aneurysm Rupture in a Child with a De Novo Variant to ANKRD17

A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report

RNAi-based screen for cuticle pigmentation inDrosophila melanogasterreveals novel regulators of brain dopamine

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