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1.
Am J Hum Genet ; 110(7): 1068-1085, 2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37352860

RESUMEN

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.


Asunto(s)
Exorribonucleasas , Histonas , Humanos , Exorribonucleasas/genética , Histonas/genética , Mutación Missense/genética , ARN Ribosómico 5.8S , ARN , ARN Mensajero/genética
2.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32822602

RESUMEN

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Asunto(s)
Atrofia/genética , Enfermedades Cerebelosas/genética , Discapacidad Intelectual/genética , Lisina Acetiltransferasa 5/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Atrofia/diagnóstico por imagen , Atrofia/fisiopatología , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/fisiopatología , Preescolar , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Reparación del ADN/genética , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Heterocigoto , Histonas/genética , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Masculino , Mutación Missense/genética , Procesamiento Proteico-Postraduccional/genética
3.
Hum Genet ; 141(8): 1423-1429, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35107634

RESUMEN

Glycosylphosphatidylinositol (GPI) functions to anchor certain proteins to the cell surface. Although defects in GPI biosynthesis can result in a wide range of phenotypes, most affected patients present with neurological abnormalities and their diseases are grouped as inherited-GPI deficiency disorders. We present two siblings with global developmental delay, brain anomalies, hypotonia, and contractures. Exome sequencing revealed a homozygous variant, NM_001035005.4:c.90dupC (p.Phe31Leufs*3) in C18orf32, a gene not previously associated with any disease in humans. The encoded protein is known to be important for GPI-inositol deacylation. Knockout of C18orf32 in HEK293 cells followed by a transfection rescue assay revealed that the PIPLC (Phosphatidylinositol-Specific Phospholipase C) sensitivity of GPI-APs (GPI-anchored proteins) was restored only by the wild type and not the mutant C18orf32. Immunofluorescence revealed that the mutant C18orf32 was localized to the endoplasmic reticulum and was also found as aggregates in the nucleus. In conclusion, we identified a pathogenic variant in C18orf32 as the cause of a novel autosomal recessive neurodevelopmental disorder with hypotonia and contractures. Our results demonstrate the importance of C18orf32 in the biosynthesis of GPI-anchors, the molecular impact of the variant on the protein function, and add a novel candidate gene to the existing repertoire of genes implicated in neurodevelopmental disorders.


Asunto(s)
Contractura , Hipotonía Muscular , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Contractura/genética , Contractura/metabolismo , Glicosilfosfatidilinositoles/metabolismo , Células HEK293 , Humanos , Hipotonía Muscular/genética , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/metabolismo , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo
4.
Mov Disord ; 37(10): 2139-2146, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35876425

RESUMEN

BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Distonía , Trastornos Distónicos , Trastornos del Movimiento , Trastornos del Neurodesarrollo , Animales , Distonía/diagnóstico , Distonía/genética , Trastornos Distónicos/genética , Trastornos del Movimiento/genética , Trastornos del Neurodesarrollo/genética , Prolina , ARN , Pez Cebra/genética
5.
Hum Genet ; 140(6): 879-884, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33386993

RESUMEN

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.


Asunto(s)
Anomalías Craneofaciales/genética , Glicosilfosfatidilinositoles/deficiencia , Deformidades Congénitas de la Mano/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Mutación Missense , Uñas Malformadas/genética , Convulsiones/genética , Adolescente , Secuencia de Aminoácidos , Animales , Consanguinidad , Anomalías Craneofaciales/metabolismo , Anomalías Craneofaciales/patología , Femenino , Expresión Génica , Glicosilfosfatidilinositoles/genética , Glicosilfosfatidilinositoles/metabolismo , Células HEK293 , Deformidades Congénitas de la Mano/metabolismo , Deformidades Congénitas de la Mano/patología , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/patología , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Proteínas de la Membrana/deficiencia , Uñas Malformadas/metabolismo , Uñas Malformadas/patología , Convulsiones/metabolismo , Convulsiones/patología , Alineación de Secuencia , Secuenciación del Exoma
6.
Clin Genet ; 100(5): 607-614, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34296759

RESUMEN

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/deficiencia , Fenotipo , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Alelos , Sustitución de Aminoácidos , Encéfalo/anomalías , Proteínas Portadoras/genética , Análisis Mutacional de ADN , Facies , Femenino , Proteínas Ligadas a GPI/biosíntesis , Estudios de Asociación Genética/métodos , Glicosilfosfatidilinositoles/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/genética , Mutación , Linaje , Embarazo , Diagnóstico Prenatal/métodos , Espasmos Infantiles/metabolismo
7.
Am J Med Genet A ; 173(3): 588-595, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28127940

RESUMEN

Smith-McCort dysplasia (SMC OMIM 615222) and Dyggve-Melchior-Clausen dysplasia (DMC OMIM 223800) are allelic skeletal dysplasias caused by homozygous or compound heterozygous mutations in DYM (OMIM 607461). Both disorders share the same skeletal phenotypes characterized by spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia. The difference rests on the presence or absence of intellectual disability, that is, intellectual disability in DMC and normal cognition in SMC. However, genetic heterogeneity was suspected in SMC. Recently, RAB33B (OMIM 605950) has been identified as the second gene for SMC. Nevertheless, only two affected families have been reported so far. Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). We also summarize the clinical, radiological, and mutation profile of RAB33B after literature mining. This report ascertains the pathogenic relationship between RAB33B and SMC. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Mutación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Proteínas de Unión al GTP rab/genética , Adulto , Alelos , Secuencia de Aminoácidos , Niño , Consanguinidad , Diagnóstico por Imagen , Facies , Heterocigoto , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Fenotipo , Proteínas/genética , Análisis de Secuencia de ADN
8.
Am J Med Genet A ; 167A(11): 2727-30, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26109321

RESUMEN

Chromosomal microdeletions and microduplications are known to cause variable clinical features ranging from apparently normal phenotype to intellectual disability, multiple congenital anomalies, and/or other variable clinical features. 7q11.23 region deletion is the cause for Williams-Beuren syndrome and duplication of same region 7q11.23 causes distinguishable clinical phenotype. Familial inheritance is known for both microdeletion and microduplication of 7q11.23 region. Here, we report a patient of paternally inherited 7q11.23 microduplication with developmental delay, macrocephaly, and structural brain malformations.


Asunto(s)
Duplicación Cromosómica/genética , Cromosomas Humanos Par 7/genética , Familia , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Fenotipo
9.
Neurol Genet ; 7(6): e631, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34703884

RESUMEN

BACKGROUND AND OBJECTIVES: To expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency. METHODS: An international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry. RESULTS: Ten novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously. DISCUSSION: Clinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.

10.
Eur J Hum Genet ; 28(4): 461-468, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31695177

RESUMEN

Neonatal progeroid syndrome, also known as Wiedemann-Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.


Asunto(s)
Codón sin Sentido , Retardo del Crecimiento Fetal/genética , Progeria/genética , ARN Polimerasa III/genética , Preescolar , Femenino , Retardo del Crecimiento Fetal/patología , Humanos , Fenotipo , Progeria/patología , Dominios Proteicos , ARN Polimerasa III/química
11.
J Pediatr Genet ; 7(1): 9-13, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29441215

RESUMEN

Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K ( CTSK ) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of CTSK . We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition.

12.
J Pediatr Genet ; 6(3): 177-180, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28794911

RESUMEN

Brachydactyly type A1 (BDA1) is characterized by short middle phalanges. We report the case of a child with a severe form of BDA1 with complete absence of the middle phalanges of all extremities. He had c.298G > A (p.D100N) mutation in IHH gene.

13.
Congenit Anom (Kyoto) ; 57(3): 83-85, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27624506

RESUMEN

We report on a consanguineous family with three pregnancies affected with Fraser syndrome. We note severe brachydactyly is a manifestation of Fraser syndrome and found a novel homozygous splice site variation c.3293-2A>T in FRAS1. We would like to highlight variable manifestations of Fraser syndrome and the presence of oligohydramnios in the antenatal period often makes prenatal diagnosis clinically challenging.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Feto/anomalías , Síndrome de Fraser/diagnóstico , Síndrome de Fraser/genética , Mutación , Fenotipo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Autopsia , Mapeo Cromosómico , Consanguinidad , Genotipo , Humanos , Linaje , Ultrasonografía Prenatal
14.
Indian J Dermatol ; 61(1): 122, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26955140

RESUMEN

In genetically and phenotypically heterogeneous conditions like ichthyosis, it is clinically not possible to predict mutation in a specific gene. Sequential testing of all the causative genes is time consuming and expensive. In consanguineous families with autosomal recessive genetically heterogeneous disorders, it is possible to narrow down the candidate gene/genes by recognizing the regions of homozygosity by a single nucleotide polymorphism (SNP) array. Here, we present a fatal case of autosomal recessive severe congenital ichthyosis born to a consanguineous couple. Two candidate genes were recognized by SNP array on banked DNA of the subject. Sequencing of these candidate genes in parents found them to be carriers of the same variation, a novel heterozygous deletion of single nucleotide in exon 8 (c. 1067delT) of ALOX12B gene. The present case illustrates the utility of DNA banking, SNP array and testing of parents to arrive at a definitive molecular diagnosis, essential for genetic counseling, and prenatal testing.

15.
Indian J Dermatol ; 61(6): 700, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27904205

RESUMEN

Focal dermal hypoplasia is a rare disorder inherited in an X-linked dominant pattern and is usually antenatally lethal in males. We report a surviving male with postzygotic de novo mutation p.E300* in exon 10 of PORCN gene with mosaicism, earlier reported in a female of Thai origin. This is the first report of this mutation from the Indian subcontinent.

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