269 results match your criteria mosaic missense

Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing.

Front Genet 2021 9;12:603195. Epub 2021 Mar 9.

Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, China.

Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Read More

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Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder.

Hum Mutat 2021 May 14;42(5):498-505. Epub 2021 Mar 14.

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.

ARHGEF9 defects lead to an X-linked intellectual disability disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males, with a few affected females reported. Up to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. Read More

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Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant.

Mol Genet Genomic Med 2021 02 14;9(2):e1574. Epub 2021 Jan 14.

Department of Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Variants in the GJB2 gene encoding the gap junction protein connexin-26 (Cx26) can cause autosomal recessive nonsyndromic hearing loss or a variety of phenotypically variable autosomal dominant disorders that effect skin and hearing, such as palmoplantar keratoderma (PPK) with deafness and keratitis-ichthyosis-deafness (KID) syndrome. Here, we report a patient with chronic mucocutaneous candidiasis, hyperkeratosis with resorption of the finger tips, profound bilateral sensorineural hearing loss, and normal hair and ocular examination. Exome analysis identified a novel missense variant in GJB2 (NM_004004. Read More

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February 2021

First radiobiological characterization of the McCune-Albright syndrome: influence of the ATM protein and effect of statins + bisphosphonates treatment.

Int J Radiat Biol 2021 6;97(3):317-328. Epub 2021 Jan 6.

Institut National des Sciences et de la Recherche Médicale, UA8 Research Unit 'Radiations: Defense, Health, Environment', Centre Anti-Cancer Léon-Bérard, Lyon, France.

Purpose: MacCune-Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, 'café-au-lait' pigmentation of the skin and multiple endocrinopathies. MAS was shown to be caused by mosaic missense somatic mutations in the gene coding for the alpha-subunit of the stimulatory G-protein. Read More

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January 2021

A population scale analysis of rare SNCA variation in the UK Biobank.

Neurobiol Dis 2021 01 8;148:105182. Epub 2020 Dec 8.

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Parkinson's disease (PD) is a complex neurodegenerative disease with a variety of genetic and environmental factors contributing to disease. The SNCA gene encodes for the alpha-synuclein protein which plays a central role in PD, where aggregates of this protein are one of the pathological hallmarks of disease. Rare point mutations and copy number gains of the SNCA gene have been shown to cause autosomal dominant PD, and common DNA variants identified using Genome-Wide Association Studies (GWAS) are a moderate risk factor for PD. Read More

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January 2021

A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1.

J Med Genet 2020 Nov 18. Epub 2020 Nov 18.

Department of Molecular Medicine and Surgery (MMK), Karolinska Institute, Stockholm, Sweden

Background: Germline pathogenic variants in cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (lobal developmental delay, ung cysts, vergrowth, ilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.

Methods: Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with RNase III domain mutations were performed. Read More

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November 2020

De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.

Hum Mutat 2021 Jan 10;42(1):66-76. Epub 2020 Nov 10.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Read More

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January 2021

Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.

Aging Cell 2020 11 23;19(11):e13251. Epub 2020 Oct 23.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Damage to the genome can accelerate aging. The percentage of aneuploid cells, that is, cells with an abnormal number of chromosomes, increases during aging; however, it is not clear whether increased aneuploidy accelerates aging. Here, we report an individual showing premature aging phenotypes of various organs including early hair loss, atrophic skin, and loss of hematopoietic stem cells; instability of chromosome numbers known as mosaic variegated aneuploidy (MVA); and spindle assembly checkpoint (SAC) failure. Read More

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November 2020

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

Am J Hum Genet 2020 11 14;107(5):977-988. Epub 2020 Oct 14.

Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.

PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. Read More

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November 2020

Asymmetric muscle weakness due to mosaic mutations.

Neurology 2020 12 28;95(24):e3406-e3411. Epub 2020 Sep 28.

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (X.L., J.L., J.B.); Inserm U1258 (X.L., J.L., J.B.); CNRS UMR7104 (X.L., J.L., J.B.); Strasbourg University (X.L., J.L., J.B.), Illkirch; CHU Raymond Poincaré (S.Q.-R., H.A., R.-Y.C.), APHP, Université de Versailles Saint Quentin en Yvelines, Garches; Laboratoire de Biochimie Génétique et Moléculaire (N.M.), IBP, CHU Grenoble Alpes; National Genotyping Center (CNG) (J.-F.D.), Genomics Institute, Office of Atomic Energy and Alternative Energies, Evry; Neuromuscular Morphology Unit (N.B.R.), Myology Institute, GHU Pitié-Salpêtrière; and Centre de Référence de Pathologie Neuromusculaire Paris-Est (N.B.R.), Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, France.

Objective: To characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.

Methods: The patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy. Read More

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December 2020

Familial hypercholesterolemia: A single-nucleotide variant (SNV) in mosaic at the low density lipoprotein receptor (LDLR).

Atherosclerosis 2020 10 28;311:37-43. Epub 2020 Aug 28.

Department of Internal Medicine, Hospital de La Princesa, Madrid, Spain.

Background And Aims: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes. Read More

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October 2020

Using an aquatic model, Xenopus laevis, to uncover the role of chromodomain 1 in craniofacial disorders.

Genesis 2021 Feb 11;59(1-2):e23394. Epub 2020 Sep 11.

Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA.

The chromodomain family member chromodomain 1 (CHD1) has been shown to have numerous critical molecular functions including transcriptional regulation, splicing, and DNA repair. Complete loss of function of this gene is not compatible with life. On the other hand, missense and copy number variants of CHD1 can result in intellectual disabilities and craniofacial malformations in human patients including cleft palate and Pilarowski-Bjornsson Syndrome. Read More

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February 2021

Complex Mosaicism of Two Distinct Mutations in a Female Patient With -Related Encephalopathy: A Case Report.

Front Genet 2020 12;11:911. Epub 2020 Aug 12.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

gene mutations were described to cause a new molecular entity within the developmental and epileptic or epileptic encephalopathies. Here, we firstly reported a patient with an unusual mosaicism for , presenting two distinct mosaic missense mutations at the same loci. Clinical trio-based whole-exome sequencing using next-generation sequencing (NGS) revealed two novel mutations in : c. Read More

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The first case of a mosaic superficial epidermolytic ichthyosis diagnosed by Ultra-Deep Sequence.

Mol Genet Genomic Med 2020 11 2;8(11):e1457. Epub 2020 Sep 2.

Department of Dermatology, Xinhua Hospital, Shanghai, China.

Background: Superficial epidermolytic ichthyosis (SEI), known as ichthyosis bullosa of Siemens (IBS; OMIM No. 146800) before, is a type of keratinopathic ichthyosis due to the KRT2 mutations (NM_000423.3; OMIM No. Read More

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November 2020

Molecular analysis of 76 Chinese hemophilia B pedigrees and the identification of 10 novel mutations.

Mol Genet Genomic Med 2020 11 1;8(11):e1482. Epub 2020 Sep 1.

The Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background: Hemophilia B (HB) is an X-linked recessive inherited bleeding disorder caused by mutations in the F9 gene that lead to plasma factor IX deficiency. To identify the causative mutations in HB, a molecular analysis of HB pedigrees in China was performed.

Methods: Using next-generation sequencing (NGS) and an in-house bioinformatics pipeline, 76 unrelated HB pedigrees were analyzed. Read More

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November 2020

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.

Exp Mol Pathol 2020 08 21;115:104471. Epub 2020 May 21.

University of Pecs, Medical School, Department of Medical Genetics, Pecs, Hungary; Szentagothai Research Center, University of Pecs, Pecs, Hungary.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Read More

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De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 06 21;106(6):830-845. Epub 2020 May 21.

Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. Read More

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Dual Deep Sequencing Improves the Accuracy of Low-Frequency Somatic Mutation Detection in Cancer Gene Panel Testing.

Int J Mol Sci 2020 May 16;21(10). Epub 2020 May 16.

Center for Clinical Genomics, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0923, Japan.

Cancer gene panel testing requires accurate detection of somatic mosaic mutations, as the test sample consists of a mixture of cancer cells and normal cells; each minor clone in the tumor also has different somatic mutations. Several studies have shown that the different types of software used for variant calling for next generation sequencing (NGS) can detect low-frequency somatic mutations. However, the accuracy of these somatic variant callers is unknown. Read More

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mutations in the X-linked gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features.

J Med Genet 2020 12 14;57(12):808-819. Epub 2020 May 14.

Division of Genomics and Genetics, Boston Children s Hospital, Boston, Massachusetts, USA.

Introduction: Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko's lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 () have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions. Read More

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December 2020

Recent Advances in Understanding the Genetic Architecture of Autism.

Annu Rev Genomics Hum Genet 2020 08 12;21:289-304. Epub 2020 May 12.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; email:

Recent advances in understanding the genetic architecture of autism spectrum disorder have allowed for unprecedented insight into its biological underpinnings. New studies have elucidated the contributions of a variety of forms of genetic variation to autism susceptibility. While the roles of de novo copy number variants and single-nucleotide variants-causing loss-of-function or missense changes-have been increasingly recognized and refined, mosaic single-nucleotide variants have been implicated more recently in some cases. Read More

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Mutations in penicillin-binding protein 2 from cephalosporin-resistant hinder ceftriaxone acylation by restricting protein dynamics.

J Biol Chem 2020 05 6;295(21):7529-7543. Epub 2020 Apr 6.

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425. Electronic address:

The global incidence of the sexually transmitted disease gonorrhea is expected to rise due to the spread of strains with decreased susceptibility to extended-spectrum cephalosporins (ESCs). ESC resistance is conferred by mosaic variants of penicillin-binding protein 2 (PBP2) that have diminished capacity to form acylated adducts with cephalosporins. To elucidate the molecular mechanisms of ESC resistance, we conducted a biochemical and high-resolution structural analysis of PBP2 variants derived from the decreased-susceptibility strain 35/02 and ESC-resistant strain H041. Read More

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Clinical histopathological features and CDKN2A/CDK4/MITF mutational status of patients with multiple primary melanomas from Bologna: Italy is a fascinating but complex mosaic.

G Ital Dermatol Venereol 2020 Mar 27. Epub 2020 Mar 27.

Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy -

Background: The incidence of cutaneous melanoma (cM) has increased in the last decades. Germline mutations in the high-penetrance melanoma susceptibility gene CDKN2A (Cyclin- dependent kinase inhibitor 2A) are associated with a younger age at diagnosis and an increased risk to develop pancreatic cancer.

Methods: We retrospectively analysed the data of patients with prior diagnosis of cM referring to our service from January 2005 to May 2017. Read More

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Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.

J Cutan Pathol 2020 Aug 6;47(8):681-685. Epub 2020 Apr 6.

Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH.

Methods: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. Read More

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High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report.

BMC Ophthalmol 2020 Feb 24;20(1):68. Epub 2020 Feb 24.

Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, 2 Verdun Street, Nedlands, WA, 6009, Australia.

Background: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. Read More

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February 2020

SCN1A-related phenotypes: Epilepsy and beyond.

Epilepsia 2019 12;60 Suppl 3:S17-S24

Reference Centre for Rare Epilepsies, Department of Paediatric Neurology, Necker Enfants Malades Hospital, Imagine Institute U1163, Paris Descartes University, Paris, France.

SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Read More

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December 2019

TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome.

Am J Med Genet A 2020 03 12;182(3):584-590. Epub 2019 Dec 12.

Clinical Genetics, Rare Disease Institute, Children's National Health System, Washington, District of Columbia.

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene encodes a transcription factor that regulates embryonic stem cell (ESC) differentiation. Its phosphorylation by the lysosomal Rag GTPase signaling pathway leads to cytoplasmic sequestration and inactivation promoting ESC differentiation and exit from pluripotency. Somatic translocations of this X-linked gene cause papillary renal cell carcinoma in which nuclear accumulation of the TFE3 oncoprotein is one of the most significant histopathologic characteristics. Read More

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The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype.

Hum Mutat 2020 03 24;41(3):591-599. Epub 2019 Dec 24.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Read More

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Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

Genet Med 2020 03 25;22(3):610-621. Epub 2019 Nov 25.

Pediatric Gastroenterology, University of Minnesota Medical School, Minneapolis, MN, USA.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Read More

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Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype.

Hum Genet 2019 Dec 4;138(11-12):1301-1311. Epub 2019 Nov 4.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. Read More

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December 2019

[A phenotypic and genetic study on β-propeller protein-associated neurodegeneration].

Zhonghua Er Ke Za Zhi 2019 Nov;57(11):830-836

Department of Neurology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China.

To summarize the clinical and genetic features of β-propeller protein-associated neurodegeneration (BPAN). The clinical data of 17 patients with BPAN with WDR45 gene variants were retrospectively collected at Children's Hospital of Fudan University, Peking University First Hospital, Capital Institute of Pediatrics, Shengjing Hospital of China Medical University and Shanghai Children's Hospital from June 2016 to December 2018, and their clinical manifestations, electroencephalogram, neuroimaging and genetics were analyzed. Seventeen cases (13 females, 4 males), aged 1. Read More

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November 2019