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1.
Toshiki Takenouchi Tomoko Uehara Kenjiro Kosaki Seiji Mizuno 《American journal of medical genetics. Part A》2018,176(3):712-714
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Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review
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Lara J. Duffney Purnima Valdez Martine W. Tremblay Xinyu Cao Sarah Montgomery Allyn McConkie‐Rosell Yong‐hui Jiang 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2018,177(4):426-433
Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10‐year‐old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3′ end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy‐terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development. 相似文献
3.
Claudia Fagali Fernando Kok Pablo Nicola Chong Kim Dbora Bertola Lílian Albano Clia P. Koiffmann 《European journal of medical genetics》2009,52(5):333-336
Sotos syndrome (MIM #117550) is an autosomal dominant condition characterized by pre and postnatal overgrowth, macrocephaly and typical facial gestalt with frontal bossing, hypertelorism, antimongoloid slant of the palpebral fissures, prominent jaw and high and narrow palate. This syndrome is also frequently associated with brain, cardiovascular, and urinary anomalies and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma. The syndrome is known to be caused by mutations or deletions of the NSD1 gene.To detect both 5q35 microdeletions and partial NSD1 gene deletions we screened 30 Brazilian patients with clinical diagnosis of Sotos syndrome by multiplex ligation dependent probe amplification.We identified one patient with a total deletion of NSD1 and neighbouring FGFR4, other with missing NSD1 exons 13-14 and another with a deletion involving FGFR4 and spanning up to NSD1 exon 17. All deletions were de novo. The two NSD1 partial deletions have not been previously reported.The clinical features of the three patients included a typical facial gestalt with frontal bossing, prominent jaw and high anterior hairline; macrocephaly, dolichocephaly, large hands; neonatal hypotonia and jaundice. All presented normal growth at birth but postnatal overgrowth. Two patients with NSD1 and FGFR4 gene deletions presented congenital heart anomalies. 相似文献
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Daniela Melis Daniel Carvalho Tina Barbaro-Dieber Alberto J. Espay Michael J. Gambello Blanca Gener Erica Gerkes Marrit M. Hitzert Hanne B. Hove Sandra Jansen Petr E. Jira Katherine Lachlan Leonie A. Menke Vinodh Narayanan Damara Ortiz Eline Overwater Renata Posmyk Keri Ramsey Alessandro Rossi Renata Lazari Sandoval Constance Stumpel Kyra E. Stuurman Viviana Cordeddu Peter Turnpenny Pietro Strisciuglio Marco Tartaglia Sheela Unger Todd Waters Clare Turnbull Raoul C. Hennekam 《Clinical genetics》2020,97(6):890-901
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer. 相似文献
7.
Xiaomin Chen Jing Jin Qiongdan Wang Huangqi Xue Na Zhang Yaoqiang Du Tao Zhang Bing Zhang Jinyu Wu Zhenwei Liu 《Human mutation》2019,40(3):281-287
Recent whole‐exome sequencing (WES) studies have demonstrated the contribution of de novo mutations (DNMs) to epileptic encephalopathies (EEs). Here, we performed WES on four trios with West syndrome and identified three loss‐of‐function DNMs in both CSNK1E (c.885+1G>A) and STXBP1 (splicing, c.1111‐2A>G; nonsense, p.(Y519X)). The splicing mutation in CSNK1E creates insertion of 116 new amino acids at position 246 followed by a premature stop codon. Both CSNK1E and STXBP1 showed a closer coexpression relationship with epilepsy candidate genes beyond that expected by chance. In addition, genes coexpressed with CSNK1E were enriched in early prenatal stages across multiple brain regions. We also found that 60 CSNK1E‐interacting genes share an association with multiple neuropsychiatric disorders, and these genes formed a significant interconnected interaction network with roles in the midbrain development. Our study supported the potential role of CSNK1E variants in EE susceptibility and expanded the phenotypic spectrum associated with CSNK1E variation. 相似文献
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Marzia Pollazzon Chiara Gelmini Stefano Giuseppe Caraffi Mahboubeh Mansouri Zahra Chavoshzadeh Simonetta Rosato Valeria Polizzi Giancarlo Gargano Marielle Alders Livia Garavelli Raoul C. Hennekam 《American journal of medical genetics. Part A》2018,176(5):1166-1174
Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals. 相似文献
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Marta Owczarek‐Lipska Aleksander Jamsheer Anna Sowińska‐Seidler Małgorzata Piotrowicz Lucjusz Jakubowski Fanny Dallèves Erik Riesch John Neidhardt Johannes R. Lemke 《American journal of medical genetics. Part A》2019,179(12):2447-2453
Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1‐related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson–Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly). 相似文献
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Helen I. Roessler Kathleen Shields Dorothy K. Grange Nine V.A.M. Knoers Gijs van Haaften Peter Hammond Mieke M. van Haelst 《American journal of medical genetics. Part A》2020,182(5):1041-1052
Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP‐sensitive potassium (KATP) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken. However, an overwhelming number of CS patients receive misdiagnoses based on an evaluation of coarse facial features. By analyzing three‐dimensional images of CS faces, we quantified facial dysmorphology in a cohort of both male and female CS patients with confirmed ABCC9 variants. Morphometric analysis of different regions of the face revealed gender‐specific significant differences in face shape. Moreover, we show that 3D facial photographs can distinguish between CS and other genetic disorders with specific facial dysmorphologies that have been mistaken for CS‐associated anomalies in the past, hence assisting in an earlier clinical and molecular diagnosis. This optimizes genetic counseling and reduces stress for patients and parents by avoiding unnecessary misdiagnosis. 相似文献
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Alison Foster Anna Zachariou Chey Loveday Tazeen Ashraf Edward Blair Jill Clayton‐Smith Huw Dorkins Alan Fryer Blanca Gener David Goudie Alex Henderson Melita Irving Shelagh Joss Vaughan Keeley Nayana Lahiri Sally Ann Lynch Sahar Mansour Emma McCann Jenny Morton Nicole Motton Alexandra Murray Katie Riches Deborah Shears Zornitza Stark Elizabeth Thompson Julie Vogt Michael Wright Trevor Cole Katrina Tatton‐Brown 《American journal of medical genetics. Part C, Seminars in medical genetics》2019,181(4):502-508
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A novel homozygous AP4B1 mutation in two brothers with AP‐4 deficiency syndrome and ocular anomalies
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Andrea Accogli Fadi F. Hamdan Chantal Poulin Christina Nassif Guy A. Rouleau Jacques L. Michaud Myriam Srour 《American journal of medical genetics. Part A》2018,176(4):985-991
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A case of severe TBCE‐negative hypoparathyroidism‐retardation‐dysmorphism syndrome: Case report and literature review
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Anna Ryabets‐Lienhard Satja Issaranggoon na Ayuthaya John M. Graham Pisit Pitukcheewanont 《American journal of medical genetics. Part A》2018,176(8):1768-1772
Hypoparathyroidism‐retardation‐dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin‐specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD‐like syndrome with no identifiable genetic etiology. We report a case of severe TBCE‐negative phenotypic HRD in a 4‐year‐old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations. 相似文献
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Yukiko Kuroda Yoko Saito Yumi Enomoto Takuya Naruto Jun Mitsui Kenji Kurosawa 《American journal of medical genetics. Part A》2023,191(8):2215-2218
PHACES syndrome is a multiple congenital disorder with unknown etiology that is characterized by Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/coarctation of the aorta, Eye anomalies, and Sternal cleft. Compound heterozygous or homozygous TMEM260 variants cause structural heart defects and renal anomalies syndrome (SHDRA). We describe a 10-year-old male patient with a PHACES-like syndrome and TMEM260 compound heterozygous variants who demonstrated overlapping phenotypes between the two syndromes. He presented with truncus arteriosus, supraumbilical raphe, ophthalmological abnormality, vertebral abnormality, borderline intellectual disability, and hearing loss. He had normal serum creatinine. In proband exome sequencing, compound heterozygous TMEM260 variants (NM_017799.4 c.1617delG p.(Trp539Cysfs*9)/c.1858C > T p.(Gln620*)) were identified. Twelve patients have been reported with TMEM260-related SHDRA: 10 had truncus arteriosus and 6 had renal failure. One previously reported patient had facial port wine nevus and another patient had supraumbilical raphe, which are the cardinal signs for PHACES syndrome. TMEM260-related SHDRA could share overlapping clinical features with PHACES syndrome. This report expands the phenotypic spectrum of a TMEM260-related disorder. 相似文献
15.
Second family provides further evidence for causation of Steel syndrome by biallelic mutations in
COL27A1
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Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus. Homozygous variants in COL27A1 were reported in an extending family from Puerto Rico. Here, we report a 5‐year‐old girl from a non‐consanguineous family with facial dysmorphism, short stature, carpal coalition, dislocation of radial heads, bilateral hip dislocation, scoliosis and vertical talus. Exome sequencing identified 2 novel compound heterozygous variants c.521_528del (p.(Cys174Serfs*34)) and c.2119C>T (p.(Arg707*)) in COL27A1 in this child and the parents were heterozygous carriers. We hence report the second molecularly proven case of Steel syndrome and the first case to be reported among non‐Puerto Rican population. Our report further validates the role of COL27A1 mutations in causation of Steel syndrome. 相似文献
16.
Nobuhiko Okamoto 《American journal of medical genetics. Part A》2019,179(5):822-826
Okamoto syndrome is characterized by severe intellectual disability, generalized hypotonia, stenosis of the ureteropelvic junction with hydronephrosis, cardiac anomalies, and characteristic facial gestalt. Several patients have been reported. The basic mechanism of Okamoto syndrome has not been clarified. Au–Kline syndrome is a new syndrome due to loss‐of‐function variants in the HNRNPK (heterogeneous nuclear ribonucleoprotein K) gene. A new patient with Okamoto syndrome visited our hospital. We noticed that the patient had features overlapping with Au–Kline syndrome. We studied the HNRNPK gene by Sanger sequencing, and identified a novel splicing variant. We suggest that Okamoto syndrome is identical to Au–Kline syndrome. 相似文献
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Anna Durkin Shadi Albaba Andrew E. Fry Jenny E. Morton Andrew Douglas Ana Beleza Denise Williams Catharina M.L. Volker‐Touw Sally A. Lynch Natalie Canham Virginia Clowes Volker Straub Katherine Lachlan Frances Gibbon Mayy El Gamal Vinod Varghese Michael J. Parker Ruth Newbury‐Ecob Peter D. Turnpenny Alice Gardham Neeti Ghali Meena Balasubramanian 《American journal of medical genetics. Part A》2020,182(7):1637-1654
With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first‐line investigation in clinical work‐up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss‐of‐function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU‐related neurodevelopmental syndrome. 相似文献
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Tara Daly Abra Roberts Edward Yang Ganeshwaran H. Mochida Olaf Bodamer 《American journal of medical genetics. Part A》2020,182(3):441-445
Kabuki syndrome is a rare, multi‐systemic disorder of chromatin regulation due to mutations in either KMT2D or KDM6A that encode a H3K4 methyltransferase and an H3K27 demethylase, respectively. The associated clinical phenotype is a direct result of temporal and spatial changes in gene expression in various tissues including the brain. Although mild to moderate intellectual disability is frequently recognized in individuals with Kabuki syndrome, the identification of brain anomalies, mostly involving the hippocampus and related structures remains an exception. Recently, the first two cases with alobar holoprosencephaly and mutations in KMT2D have been reported in the medical literature. We identified a de novo, pathogenic KMT2D variant (c.6295C > T; p.R2099X) using trio whole‐exome sequencing in a 2‐year‐old female with lobar holoprosencephaly, microcephaly and cranio‐facial features of Kabuki syndrome. This report expands the spectrum of brain anomalies associated with Kabuki syndrome underscoring the important role of histone modification for early brain development. 相似文献
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Diffuse Midline Gliomas with Histone H3‐K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations
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David A. Solomon Matthew D. Wood Tarik Tihan Andrew W. Bollen Nalin Gupta Joanna J. J. Phillips Arie Perry 《Brain pathology (Zurich, Switzerland)》2016,26(5):569-580
Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high‐grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3‐K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)‐like foci, neuropil‐like islands, pilomyxoid features, ependymal‐like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)‐like areas. In this series, histone H3‐K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co‐occurred with BRAF‐V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10. 相似文献