De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies

Platzer, Konrad; Sticht, Heinrich; Edwards, Stacey L.; Allen, William P.; Angione, Kaitlin M.; Bonati, Maria Teresa; Brasington, Campbell K.; Cho, Megan T.; Demmer, Laurie A.; Falik‐Zaccai, Tzipora C.; Gamble, Candace; Hellenbroich, Yorck; Iascone, Maria; Kok, Fernando; Mahida, Sonal; Mandel, Hanna; Marquardt, Thorsten; McWalter, Kirsty; Panis, Bianca; Pepler, Alexander; Pinz, Hailey; Ramos, Luiza; Shinde, Deepali N.; Smith‐Hicks, Constance; Stegmann, Alexander P.A.; Stöbe, Petra; Stumpel, Constance T. R. M.; Wilson, Carolyn M.; Lemke, Johannes R.; Donato, Nataliya Di; Miller, Kenneth G.; Jamra, Rami Abou

doi:10.1016/j.ajhg.2018.12.008

Cited by 51 publications

(68 citation statements)

References 43 publications

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“…Aicardi syndrome was the most common associated syndrome with 62 cases including one male, followed by Dandy–Walker syndrome, 24 cases. Over 200 genetic syndromic conditions associated with ACC are listed in the Online Mendelian Inheritance in Man (OMIM) database, including syndromes with identified genes, syndromes with ACC seen consistently, no gene yet identified, and syndromes with ACC seen occasionally (Burgemeister et al, ; Lefebvre et al, ; Palmer & Mowat, ; Paul et al, ; Platzer et al, ; Romaniello et al, ; Wojcik et al, ).…”

Section: Discussionmentioning

confidence: 99%

Associated anomalies in cases with agenesis of the corpus callosum

Stoll

Dott

Roth

2019

American J of Med Genetics Pt A

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Agenesis of corpus callosum (ACC) is an uncommon congenital anomaly, its etiology is unclear and its pathogenesis is controversial. Cases with ACC often have other non-ACC associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population.The associated anomalies in cases with ACC were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 99 cases with ACC, representing a prevalence of 2.56 per 10,000, 73 (73.7%) had associated anomalies. There were 16 (16.2%) cases with chromosomal abnormalities, and 13 (13.2%) nonchromosomal recognized dysmorphic conditions including syndromes two each: Aicardi, Dandy-Walker, and fetal alcoholism. Forty-four (44.4%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the musculoskeletal, the urogenital, the central nervous, the cardiovascular, and the digestive systems were the most common other anomalies in the cases with MCA.The anomalies associated with ACC could be classified into a recognizable malformation syndrome in 29 out of the 73 cases (39.7%) with associated anomalies. This study included special strengths: it is population-based, each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, three of four cases, emphasizes the need for a screening for other anomalies in cases with ACC. K E Y W O R D Sagenesis of corpus callosum, brain malformations, central nervous system anomalies, congenital anomalies, multiple congenital anomalies

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Section: Discussionmentioning

confidence: 99%

Associated anomalies in cases with agenesis of the corpus callosum

Stoll

Dott

Roth

2019

American J of Med Genetics Pt A

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“…CNVs are structural mutations that occur when genomic regions are duplicated or deleted compared to the reference genome 7 . Several large, rare CNVs have been robustly associated with increased risk for neurodevelopmental disorders (NDDs) including intellectual disability (ID), developmental delay (DD), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and multiple congenital anomalies 8,9 . Of all childhood cases referred for chromosomal microarray analysis (CMA), 10% carry a pathogenic CNV 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

Farrell

Lichtenstein

Harner³

et al. 2020

Transl Psychiatry

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The 15q11.2 BP1-BP2 (Burnside-Butler) deletion is a rare copy number variant impacting four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5), and carries increased risks for developmental delay, intellectual disability, and neuropsychiatric disorders (attention-deficit/hyperactivity disorder, autism, and psychosis). In this case report (supported by extensive developmental information and medication history), we present the complex clinical portrait of a 44-year-old woman with 15q11.2 BP1-BP2 deletion syndrome and chronic, treatment-resistant psychotic symptoms who has resided nearly her entire adult life in a long-term state psychiatric institution. Diagnostic and treatment implications are discussed.

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“…NDD is a highly heterogeneous disease group 25 with a large number of biological pathways affected by pathogenic variants, reflecting the complexity of normal brain development. A microdeletion on chromosome 17, comprising TAOK1, had nominated TAOK1 as a potential candidate gene for developmental delay and microcephaly.…”

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confidence: 99%

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

Dulovic-Mahlow

Trinh

Kandaswamy

et al. 2019

The American Journal of Human Genetics

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De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n ¼ 2,030) versus without (n ¼ 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

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De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies

Cited by 51 publications

References 43 publications

Associated anomalies in cases with agenesis of the corpus callosum

Associated anomalies in cases with agenesis of the corpus callosum

Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

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