RESUMEN
Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.
Asunto(s)
Histonas , Fenotipo , Humanos , Masculino , Femenino , Histonas/genética , Niño , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Preescolar , Adolescente , Adulto , Discapacidad Intelectual/genética , Discapacidad Intelectual/patologíaRESUMEN
Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically, the focus of the genetic elucidation of non-specific ID has been on genes on the X chromosome, and recent research has brought attention to the growing contribution of autosomal genes. In addition, next-generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID. We performed NGS analysis of a total of 90 genes implicated in non-specific ID. The 90 genes included 56 X-linked genes and 34 autosomal genes. Pathogenic variants were identified in 11 of 52 (21%) patient samples. Nine of the eleven cases harbored mutations in autosomal genes including AP4B1, STXB1, SYNGAP1, TCF4 and UBE3A. Our mutation-positive cases provide further evidence supporting the prevalence of autosomal mutations in patients referred for non-specific ID testing and the utility of their inclusion in multi-gene panel analysis.
RESUMEN
RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was â¼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.
Asunto(s)
Cromosomas Humanos Par 19/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , MAP Quinasa Quinasa 2/genética , Fenotipo , Transducción de Señal/genética , Adolescente , Western Blotting , Preescolar , Estudios de Cohortes , Facies , Humanos , Lactante , MAP Quinasa Quinasa 2/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteína Oncogénica p21(ras)/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Eliminación de Secuencia/genéticaAsunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 1 , Discapacidades del Desarrollo/genética , Convulsiones/genética , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico , Cara/anomalías , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Fenotipo , Convulsiones/diagnósticoRESUMEN
The objective of our article is to illustrate the earliest prenatal sonographic diagnosis of femoral-facial syndrome (FFS) and to illustrate the spectrum of clinical manifestations of this condition. We present serial sonographic evaluation with 3D evaluation in two fetuses diagnosed prenatally with FFS and the postnatal findings in three patients (one fetus following pregnancy interruption and two newborns one of whom was diagnosed prenatally) with FFS. The two patients with prenatally diagnosed FFS were found to have femoral shortening and characteristic facial features, one 12 weeks of gestation, and one at 15 weeks of gestation. The sonographic findings in the two prenatally diagnosed patients were confirmed after delivery. We also present a third patient who was diagnosed at delivery in whom the diagnosis was missed at a routine prenatal sonogram at 19 weeks of gestation. The patients reported herein expand the clinical spectrum of FFS. The utility of sonographic evaluation in diagnosis of the facial appearance and of the bony abnormalities in this condition is emphasized.
Asunto(s)
Anomalías Múltiples , Anomalías Craneofaciales/diagnóstico , Fémur/anomalías , Diagnóstico Prenatal , Adulto , Femenino , Fémur/embriología , Humanos , Recién Nacido , Masculino , Embarazo , SíndromeRESUMEN
BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
Asunto(s)
Anomalías Múltiples , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Discapacidades del Desarrollo , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Inversión Cromosómica , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Cara/patología , Femenino , Humanos , Lactante , Masculino , Hipotonía Muscular/epidemiología , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Prevalencia , Adulto Joven , Proteínas tauRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the DHCR7 gene. Previous studies estimated the prevalence of SLOS between 1 in 10,000 to 1 in 70,358 based on case frequency surveys. Although panethnic, SLOS appears to be most frequent in Central European populations (Czech Republic 1 in 10,000, Slovakia 1 in 15,000 - 1 in 20,000). In Polish individuals with SLOS two DHCR7 mutations, c.452G>A (p.Trp151X) and c.976G>T (p.Val326Leu), account for 65.2% of all observed DHCR7 mutations. We analyzed 2169 samples for the p.Trp151X mutation and 2087 for the p.Val326Leu mutation. The combined carrier frequency of these two mutations of was 2.40+/-0.32%, yielding a calculated incidence of SLOS in Poland of 2.5 4x10(-4)-4.3 5x10(-4) (1 in 2,300 to 1 in 3,937) placing SLOS among the most common recessive genetic disorders in Poland.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Síndrome de Smith-Lemli-Opitz/epidemiología , Síndrome de Smith-Lemli-Opitz/genética , Alelos , Sustitución de Aminoácidos , Femenino , Genes Recesivos , Pruebas Genéticas , Heterocigoto , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Mutación Puntual , Polonia/epidemiología , Síndrome de Smith-Lemli-Opitz/enzimologíaRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by reduced activity of 7-dehydrocholesterol (7DHC) reductase, resulting in a decreased level of cholesterol and increased concentrations of 7DHC and 8DHC in body fluids and tissues. Ten pregnancies at 25% risk of SLOS underwent prenatal testing. Diagnostic studies included DHCR7 mutation analysis in chorionic villus samples, amniotic fluid sterol analysis and serial measurements of oestriol (E3), pregnanetriol (PT), 7-dehydropregnanetriol (7DHPT) and 8-dehydroesteriol (8DHE3) concentrations in maternal urine samples obtained between 9 and 20 weeks of gestation. All tests were diagnostic and revealed nine unaffected foetuses (two normal homozygotes and seven DHCR7 heterozygotes) and one affected foetus. In the affected pregnancy, 7DHC and 8DHC in amniotic fluid were 9.87 and 3.7 microg/ml, respectively [reference range (RR) 0.0026 +/- 0.0015 microg/ml and not detectable, respectively] and maternal urinary steroid analyses showed increased ratios of 7DHPT/PT and 8DHE3/E3 of 0.74 and 1.7, respectively (RR 0-0.0147 and 0-0.019). In the heterozygous foetuses, 7DHPT/PT and 8DHE3/E3 ratios did not exceed those found in 48 normal controls. This is the first series of prenatal diagnostic testing for SLOS where non-invasive biochemical testing was performed in tandem with invasive diagnostic testing. We conclude that steroid measurements in maternal urine are a reliable means of prenatal diagnosis for SLOS.
Asunto(s)
Deshidrocolesteroles/orina , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/orina , Diagnóstico Prenatal , Síndrome de Smith-Lemli-Opitz/diagnóstico , Adulto , Líquido Amniótico/metabolismo , Muestra de la Vellosidad Coriónica , Deshidrocolesteroles/metabolismo , Estriol/metabolismo , Estriol/orina , Familia , Femenino , Cromatografía de Gases y Espectrometría de Masas , Genotipo , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Fenotipo , Embarazo , Pregnanotriol/metabolismo , Pregnanotriol/orina , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/metabolismoAsunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 9/genética , Genotipo , Fenotipo , Niño , Preescolar , Anomalías Craneofaciales/genética , Citogenética , Humanos , Hibridación Fluorescente in Situ , Lactante , Trastornos del Desarrollo del Lenguaje , Microcefalia/genética , SíndromeAsunto(s)
Codón sin Sentido/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , ARN Mensajero/metabolismo , Síndrome de Smith-Lemli-Opitz/genética , Adulto , Alelos , Células Cultivadas , Colesterol/metabolismo , Codón sin Sentido/genética , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Recién Nacido , Masculino , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Fenotipo , Embarazo , Síndrome de Smith-Lemli-Opitz/sangre , Síndrome de Smith-Lemli-Opitz/diagnóstico , Síndrome de Smith-Lemli-Opitz/metabolismoRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the DHCR7 gene. Thirty-seven ethnic Polish patients with SLOS underwent mutation analysis. The mutation frequencies in Polish patients were significantly different from those observed in Western European populations. Two mutations, W151X (22/68 alleles, 32%) and V326L (19/68 alleles, 28%), accounted for 60% of all observed in our cohort. Two missense mutations L68P and L360P have not been reported previously. In total, we report 15 DHCR7 mutations identified in Polish patients. By comparing clinical severity scores and the biochemical and molecular data, a genotype-phenotype correlation was attempted. In compound heterozygotes with one null mutation, the phenotype severity depends on the localization and type of the second mutation: mild phenotypes are correlated with mutations affecting the putative transmembrane domains TM1-TM6 or CT regions and severe phenotypes with mutations localized in TM7 and 4L region. The phenotypic differences of patients with the same genotype suggest that severity of the disease may be affected by other factors.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Síndrome de Smith-Lemli-Opitz/genética , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Fenotipo , PoloniaRESUMEN
The chiral metabolite 2-hydroxysebacic acid (2-HS) is considered to be an important diagnostic marker for peroxisomal disorders. The pathway of formation of 2-HS, excreted in increased amounts in patients with peroxisomal diseases, is not absolutely clear. Moreover, there is no information about the enantiomeric distribution of 2-HS in human urine. Here, we describe the stereodifferentiation of 2-HS in urine samples of nine patients with Zellweger syndrome (ZS), and for the first time in urine samples of premature infants fed a medium-chain triglyceride (MCT)-containing diet. Using enantioselective multidimensional gas chromatography-mass spectrometry, an increased excretion of 2R-HS was observed in all investigated ZS patients. 2-HS was also present in urine samples of premature infants fed MCT. Analogously to the ZS patients, a dominant 2R-HS excretion in the urine samples of the premature infants was identified. The formation of 2-HS is expected to result from the same or similar pathways as described for ZS patients. Additionally, we determined the absolute configuration of urinary 3-hydroxysebacic acid (3-HS) in the cases investigated. The enantioselective analysis provides further information for the diagnosis and treatment of patients with impaired peroxisomal fatty acid oxidation. Further insight into the metabolic origin and the biochemical pathway leading to these urinary metabolites is provided.
Asunto(s)
Ácidos Decanoicos/orina , Hidroxiácidos/orina , Recien Nacido Prematuro/orina , Triglicéridos/uso terapéutico , Síndrome de Zellweger/dietoterapia , Síndrome de Zellweger/orina , Preescolar , Cromatografía de Gases , Dieta , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Espectrometría de Masas , EstereoisomerismoRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the 7-dehydrocholesterol reductase gene, DHCR7. The diagnosis is based on the biochemical findings of elevated plasma 7-dehydrocholesterol (7DHC) levels. Adrenal insufficiency with hyponatremia has been reported in 3 patients with severe SLOS; in those cases it was thought to be caused by aldosterone deficiency because it responded to mineralocorticoid replacement. We present a fourth patient with a severe form of SLOS and adrenal insufficiency who had unexplained persistent hypertension, a combination of signs that has not been reported previously in SLOS.
Asunto(s)
Insuficiencia Suprarrenal/congénito , Hipertensión/congénito , Síndrome de Smith-Lemli-Opitz/diagnóstico , Colesterol/sangre , Deshidrocolesteroles/sangre , Humanos , Recién Nacido , MasculinoRESUMEN
Smith-Lemli-Opitz syndrome (RHS) (SLOS, OMIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3beta-hydroxysterol Delta(7)-Delta(8)-reductase gene, DHCR7. We report a fetus with holoprosencephaly and multiple congenital anomalies who was homozygous for the IVS8-1G-->C mutation. Following termination of pregnancy, both the elevated amniotic fluid 7-dehydrocholesterol level and the DHCR7 mutations were demonstrated. Two other newborn infants with IVS8-1G-->C/IVS8-1G-->C genotype are described. This report illustrates a severe phenotypic extreme of SLOS associated with a null genotype, underscores the complex relationship between SLOS and holoprosencephaly, and discusses the possible pathogenetic mechanisms of the development of holoprosencephaly in SLOS.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Síndrome de Smith-Lemli-Opitz/genética , Secuencia de Bases , Resultado Fatal , Muerte Fetal , Feto , Genotipo , Holoprosencefalia/patología , Homocigoto , Humanos , Recién Nacido , Masculino , Oxidorreductasas/genética , Mutación Puntual , Síndrome de Smith-Lemli-Opitz/patologíaRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is an inherited multiple malformation syndrome caused by enzymatic deficiency of 3beta-hydroxysterol-Delta(7)-reductase (DHCR7). SLOS is thought to be most common among European Caucasians, with an incidence of 1 in 20,000 to 1 in 30,000 births. To define the carrier rate and ethnic distribution of SLOS, we screened DNA samples from 2,978 unrelated individuals for the most common SLOS mutation (IVS8-1G-->C). Twenty-four heterozygotes of the IVS8-1G-->C mutation were detected in 2,978 individuals of European Caucasian and Black backgrounds. For European Caucasians, the carrier rate for SLOS may be as high as 1 in 30, suggesting an incidence of 1 in 1,700 to 1 in 13,400. This high number is supported by the recent observation of newborn and prenatal incidence of 1 in 22,000 in the Caucasian population. Ours is the first report of the IVS8-1G-->C mutation in persons of African ancestry. Published 2001 Wiley-Liss, Inc.
Asunto(s)
Frecuencia de los Genes/genética , Mutación/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Síndrome de Smith-Lemli-Opitz/enzimología , Síndrome de Smith-Lemli-Opitz/genética , Europa (Continente)/epidemiología , Europa (Continente)/etnología , Tamización de Portadores Genéticos , Pruebas Genéticas , Humanos , Síndrome de Smith-Lemli-Opitz/etnologíaRESUMEN
Smith-Lemli-Opitz syndrome (OMIM 270400) (SLOS) is caused by inherited enzymatic deficiency of 3beta-hydroxysterol-Delta7-reductase (7-dehydrocholesterol-Delta7-reductase, DHCR7). SLOS is diagnosed clinically by the demonstration of elevated levels of 7-dehydrocholesterol (7DHC) in body fluids or tissues. SLOS is associated with mental retardation of variable degree and severe behavior abnormalities. The physical abnormalities range from minor facial anomalies to lethal malformations of the central nervous system, heart, kidneys, and other organs. The exact incidence of SLOS is not known. Although there exist estimates of the incidence of SLOS ranging from 1 in 20,000 to 1 in 60,000, no prospective studies of the incidence of SLOS, based on the clinical data and biochemical diagnosis of SLOS, have been performed. Five unrelated cases of SLOS were diagnosed in Ontario during a 12-month period. The diagnoses were made based on the demonstration of elevated 7DHC in plasma or amniotic fluid. The birth rate for Ontario for that period was 132,000 births. The incidence of SLOS in Ontario was at least 1 in 26,500 pregnancies in 1999-2000. Given that 86% of the population of Ontario is of European origin, the incidence of SLOS in the Ontario population of European origin was at least 1 in 22,700. As infants with mild forms of SLOS born during this period may remain undiagnosed, these numbers likely are underestimates. This observation has implications for prenatal and newborn screening for this potentially treatable inherited disorder.
Asunto(s)
Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas/genética , Síndrome de Smith-Lemli-Opitz/genética , Deshidrocolesteroles/sangre , Humanos , Incidencia , Mutación , Ontario/epidemiología , Oxidorreductasas/deficiencia , Índice de Severidad de la Enfermedad , Síndrome de Smith-Lemli-Opitz/enzimología , Síndrome de Smith-Lemli-Opitz/epidemiologíaRESUMEN
The brief history of the Smith-Lemli-Opitz syndrome (SLOS) (MIM 270400) reflects that of latter 20th century dysmorphology and biochemical and molecular genetics: from its first description as a rare but characteristic multiple malformation syndrome known only to a handful of dysmorphologists, to a relatively common Garrodian defect with a complex molecular basis that has captured the attention of researchers and basic scientists from the fields as diverse as embryology, developmental biology, sterol biochemistry, epidemiology, and teratology. The discovery of the underlying biochemical defect - deficiency of 3beta-hydroxysteroid-Delta7-reductase (DHCR7), an enzyme catalyzing the last step of cholesterol biosynthesis, and the resultant generalized cholesterol deficiency - has led to an explosion of knowledge of this biochemical pathway and to a paradigm shift in the recognition of metabolic deficiencies as causes of dysmorphic syndromes. Characterization of the human DHCR7 gene and the identification of mutations in patients with SLOS have revealed a complex picture of molecular heterogeneity and provided insights into the structure and function of DHCR7. SLOS is the first metabolic malformation syndrome with profound effects on the body plan, and its discovery has paved the way to the discovery of a number of other defects of the cholesterol synthetic pathway.