Hypotrichosis‐lymphedema‐telangiectasia syndrome: Report of ileal atresia associated with a SOX18 de novo pathogenic variant and review of the phenotypic spectrum

Objective:To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.Methods:We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.Results:We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.Conclusions:The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

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Beneficial effects of the ketogenic diet on drug-resistant epileptic encephalopathy associated with a de novo NBEA pathogenic variant

Epileptic Disorders ◽

10.1684/epd.2021.1327 ◽

2021 ◽

Vol 23 (5) ◽

pp. 739-743

Author(s):

Silvia Schiavoni ◽

Carlotta Spagnoli ◽

Susanna Rizzi ◽

Grazia Gabriella Salerno ◽

Daniele Frattini ◽

...

Keyword(s):

Ketogenic Diet ◽

De Novo ◽

Epileptic Encephalopathy ◽

Pathogenic Variant ◽

Drug Resistant ◽

Beneficial Effects

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Exome sequencing identified a de novo frameshift pathogenic variant of CTBP1 in an extremely rare case of HADDTS

Journal of Genetics ◽

10.1007/s12041-021-01315-0 ◽

2021 ◽

Vol 100 (2) ◽

Author(s):

Hossein Jafari Khamirani ◽

Sina Zoghi ◽

Ali Saber Sichani ◽

Mehdi Dianatpour ◽

Sanaz Mohammadi ◽

...

Keyword(s):

Exome Sequencing ◽

Rare Case ◽

De Novo ◽

Pathogenic Variant

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Role of PUF60 gene in Verheij syndrome: a case report of the first Chinese Han patient with a de novo pathogenic variant and review of the literature

BMC Medical Genomics ◽

10.1186/s12920-018-0421-3 ◽

2018 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Qiong Xu ◽

Chun-yang Li ◽

Yi Wang ◽

Hui-ping Li ◽

Bing-bing Wu ◽

...

Keyword(s):

Case Report ◽

De Novo ◽

Pathogenic Variant ◽

Review Of The Literature ◽

Chinese Han

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Pierquin Syndrome: Report of a New Case

Journal of Pediatric Neurology ◽

10.1055/s-0040-1710397 ◽

2020 ◽

Author(s):

Francisco Cammarata-Scalisi ◽

Colin Eric Willoughby ◽

María Angelina Lacruz- Rengel ◽

Enrico Silvio Bertini ◽

Michele Callea

Keyword(s):

Congenital Heart ◽

Autosomal Recessive ◽

Malformation Syndrome ◽

Postaxial Polydactyly ◽

Phenotypic Spectrum ◽

Dandy Walker Malformation ◽

Rare Malformation ◽

Walker Malformation ◽

Genetic Entity ◽

Syndrome Report

AbstractPierquin syndrome is a rare genetic entity characterized by the association of Dandy–Walker malformation and postaxial polydactyly. The incidence is uncertain with only six cases previously reported in the literature. In this study, we reported a new case of Pierquin syndrome born from consanguineous parents, characterized by Dandy–Walker malformation, postaxial polydactyly, and congenital heart disease. The case reinforces an autosomal recessive modality of inheritance and expands the phenotypic spectrum of this rare malformation syndrome.

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A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

BioMed Research International ◽

10.1155/2021/6661860 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Lulu Yan ◽

Ru Shen ◽

Zongfu Cao ◽

Chunxiao Han ◽

Yuxin Zhang ◽

...

Keyword(s):

De Novo ◽

Genetic Disorder ◽

Neurodevelopmental Disorder ◽

Three Dimensional ◽

Missense Variant ◽

Pathogenic Variant ◽

Dimensional Structure ◽

Chinese Family ◽

Speech Impairment ◽

Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

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A Novel Pathogenic Variant in the MN1 Gene in a Patient Presenting with Rhombencephalosynapsis and Craniofacial Anomalies, Expanding MN1 C-terminal Truncation Syndrome

Journal of Pediatric Genetics ◽

10.1055/s-0041-1728650 ◽

2021 ◽

Author(s):

Carmen Palma ◽

Pérez Mohand Patricia ◽

José M. Lezana ◽

Jaime Cruz ◽

Juan F. Quesada ◽

...

Keyword(s):

De Novo ◽

Pathogenic Variant ◽

Craniofacial Anomalies ◽

Osteoblast Proliferation ◽

Terminal Portion ◽

Transcription Activator ◽

Palate Development ◽

Partial Rhombencephalosynapsis ◽

And Function ◽

Craniofacial Defects

AbstractMeningioma-1 is a transcription activator that regulates mammalian palate development and is required for appropriate osteoblast proliferation, motility, differentiation, and function. Microdeletions involving the MN1 gene have been linked to syndromes including craniofacial anomalies, such as Toriello–Carey syndrome. Recently, truncating variants in the C-terminal portion of the MN1 transcriptional factor have been linked to a characteristic and distinct phenotype presenting with craniofacial anomalies and partial rhombencephalosynapsis, a rare brain malformation characterized by midline fusion of the cerebellar hemispheres with partial or complete loss of the cerebellar vermis. It has been called MN1 C-terminal truncation (MCTT) syndrome or CEBALID (Craniofacial defects, dysmorphic Ears, Brain Abnormalities, Language delay, and Intellectual Disability) and suggested to be caused by dominantly acting truncated protein MN1 instead of haploinsufficiency. As a proto-oncogene, MN1 is also involved in familial meningioma. In this study, we present a novel case of MCTT syndrome in a female patient presenting with craniofacial anomalies and rhombencephalosynapsis, harboring a de novo pathogenic variant in the MN1 gene: c.3686_3698del, p.(Met1229Argfs*87).

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