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1.
Cells ; 11(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36010612

RESUMO

xa13 is a recessive pleiotropic gene that positively regulates rice disease resistance and negatively regulates rice fertility; thus, seriously restricting its rice breeding application. In this study, CRISPR/Cas9 gene-editing technology was used to delete the Xa13 gene promoter partial sequence, including the pathogenic bacteria-inducible expression element. Rice with the edited promoter region lost the ability for pathogen-induced gene expression without affecting background gene expression in leaves and anthers, resulting in disease resistance and normal yield. The study also screened a family of disease-resistant and normal fertile plants in which the target sequence was deleted and the exogenous transgene fragment isolated in the T1 generation (transgene-free line). Important agronomic traits of the T2 generation rice were examined. T2 generation rice with/without exogenous DNA showed no statistical differences compared to the wild type in heading stage, plant height, panicles per plant, panicle length, or seed setting rate in the field. Two important conventional rice varieties, namely Kongyu131 (KY131, Geng/japonica) and Huanghuazhan (HHZ, Xian/indica), were successfully transformed, and disease-resistant and fertile materials were obtained. Currently, these are the two important conventional rice varieties in China that can be used directly for production after improvement. Expression of the Xa13 gene in the leaves of transgenic rice (KY-PD and HHZ-PD) was not induced after pathogen infection, indicating that this method can be used universally and effectively to promote the practical application of xa13, a recessive disease-resistant pleiotropic gene, for rice bacterial blight resistance. Our study on the regulation of gene expression by editing noncoding regions of the genes provides a new idea for the development of molecular design breeding in the future.


Assuntos
Oryza , Resistência à Doença/genética , Edição de Genes , Genes Recessivos , Oryza/genética , Oryza/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia
2.
Mol Genet Genomics ; 297(5): 1185-1193, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35869994

RESUMO

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary deafness. It is genetically highly heterogeneous and about 89 gene loci and 76 gene's mutations have been implicated in the etiology of ARNSHL. Molecular basis of ARNSHL remains unresolved in 60% of cases and gene mutations are unknown for 23 of 89 reported loci. Techniques used to identify reported ARNSHL gene mutations can be divided into position-dependent and position-independent approaches. The localization of the loci has been facilitated by homozygosity mapping or linkage studies using STR or SNP genotyping in large consanguineous families. First few genes identified for hearing loss exhibited such wide diversity of function and expression patterns that candidate gene approach was not a viable option. The mapping of the disorder to a chromosomal location has been followed by Sanger sequencing of all genes in the target region or confining of the massively parallel sequencing data analyses to the linkage region. Sometimes genes located in the linkage interval were prioritized because there was a reported orthologs with mutations causing hearing loss in mouse or when mutations in the gene caused a related disorder. Position-independent approaches involving use of mouse subtractive cochlear libraries, forward genetic screening, and position-independent analyses of massively parallel sequencing data have helped identify 17 of 68 reported ARNSHL gene mutations. A thorough study of the strategies used in the identification of reported ARNSHL genes and of their relative success can help increase the success rate of future studies.


Assuntos
Surdez , Perda Auditiva , Animais , Surdez/genética , Genes Recessivos , Perda Auditiva/genética , Camundongos , Mutação , Linhagem
3.
Transl Vis Sci Technol ; 11(7): 6, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816039

RESUMO

Purpose: The purpose of this study was to investigate the genetic and clinical characteristics of eyes shut homolog (EYS)-associated retinitis pigmentosa (RP). Methods: This was a retrospective cross-sectional observational study of 36 patients with EYS-associated autosomal recessive RP (arRP). Results: The gene sequencing results revealed that c.6416G>A (p.Cys2139Tyr) and c.7228+1G>A were the two most predominant variants in our cohort and that variants near the C-terminus, which contains alternating laminin and epidermal growth factor (EGF) domains, accounted for the majority of the allele counts (58 of a total of 72) and relative allele frequencies (81%). Over half of the patients presented with pericentral-type RP (n = 19, 60%), which frequently occurred in combination with macular lesions (n = 10, 52%). Patients having both variants within the alternating laminin and EGF domains near the C-terminus had a more severe disease progression (average 0.045 logMAR increase per year) than those having one variant in the N-terminus and the other in the C-terminus (average 0.001 logMAR increase per year). Conclusions: Pericentral RP was the major phenotype in patients with EYS-associated arRP. There was also a statistically significant relationship between the location of the variants and the severity of the disease. Translational Relevance: This study may aid patients with EYS-associated arRP to predict future vision acuity based on their genetic and clinical features.


Assuntos
Proteínas do Olho , Retinite Pigmentosa , Estudos Transversais , Análise Mutacional de DNA , Fator de Crescimento Epidérmico/genética , Proteínas do Olho/genética , Genes Recessivos , Genótipo , Humanos , Laminina/genética , Mutação , Linhagem , Retinite Pigmentosa/genética , Estudos Retrospectivos
4.
PLoS One ; 17(6): e0268078, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35709191

RESUMO

Hearing impairment (HI) is a heterogeneous condition that affects many individuals globally with different age groups. HI is a genetically and phenotypically heterogeneous disorder. Over the last several years, many genes/loci causing rare autosomal recessive and dominant forms of hearing impairments have been identified, involved in various aspects of ear development. In the current study, two affected individuals of a consanguineous family exhibiting autosomal recessive nonsyndromic hearing impairment (AR-NSHI) were clinically and genetically characterized. The single affected individual (IV-2) of the family was subjected to whole-exome sequencing (WES) accompanied by traditional Sanger sequencing. Clinical examinations using air conduction audiograms of both the affected individuals showed profound hearing loss across all frequencies. WES revealed a homozygous missense variant (c.44G>C) in the SIX5 gene located on chromosome 19q13.32. We report the first case of autosomal recessive NSHI due to a biallelic missense variant in the SIX5 gene. This report further supports the evidence that the SIX5 variant might cause profound HI and supports its vital role in auditory function. Identification of novel candidate genes might help in application of future gene therapy strategies that may be implemented for NSHI, such as gene replacement using cDNA, gene silencing using RNA interference, and gene editing using the CRISPR/Cas9 system.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Surdez/genética , Genes Recessivos , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Homozigoto , Humanos , Mutação , Mutação de Sentido Incorreto , Linhagem
6.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682719

RESUMO

Hearing is an important human sense for communicating and connecting with others. Partial deafness (PD) is a common hearing problem, in which there is a down-sloping audiogram. In this study, we apply a practical system for classifying PD patients, used for treatment purposes, to distinguish two groups of patients: one with almost normal hearing thresholds at low frequencies (PDT-EC, n = 20), and a second group with poorer thresholds at those same low frequencies (PDT-EAS, n = 20). After performing comprehensive genetic testing with a panel of 237 genes, we found that genetic factors can explain a significant proportion of both PDT-EC and PDT-EAS hearing losses, accounting, respectively, for approx. one-fifth and one-half of all the cases in our cohort. Most of the causative variants were located in dominant and recessive genes previously linked to PD, but more than half of the variants were novel. Among the contributors to PDT-EC we identified OSBPL2 and SYNE4, two relatively new hereditary hearing loss genes with a low publication profile. Our study revealed that, for all PD patients, a postlingual hearing loss more severe in the low-frequency range is associated with a higher detection rate of causative variants. Isolating a genetic cause of PD is important in terms of prognosis, therapeutic effectiveness, and risk of recurrence.


Assuntos
Implante Coclear , Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Receptores de Esteroides , Surdez/genética , Genes Recessivos , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Humanos , Receptores de Esteroides/genética
7.
Mol Ther ; 30(8): 2664-2679, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35690907

RESUMO

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.


Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Animais , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Epidermólise Bolhosa Distrófica/terapia , Genes Recessivos , Queratinócitos/metabolismo , Camundongos , Mutação , Pele/metabolismo
8.
Clin Genet ; 102(2): 87-97, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35532184

RESUMO

An equitable approach by the American College of Medical Genetics and Genomics (ACMG) has recently recommended carrier screening for genes associated with moderate to severe autosomal recessive conditions with a carrier frequency of ≥1/200 in the Genome Aggregation Database exomes (gnomADv2.0.2). We analyzed carrier frequencies in gnomADv3.1.1 genomes representing diverse populations. ClinVar data on 35 996 pathogenic/likely pathogenic variants in 419 genes were used to estimate the gnomAD frequency of heterozygous carriers. We found that ninety-two genes had a carrier frequency of ≥1/200, of which 63 were shared between v3.1.1 and v2.0.2 and 29 were new in v3.1.1. Addition of new populations (Amish, Finnish and Middle Eastern) increased the number of new genes with a carrier frequency of ≥1/200 to 71. Changes in carrier frequencies were attributed to new gnomAD populations, different sample sizes, new ClinVar data, and technical differences between exomes and genomes. This study highlights the dynamic changes in carrier frequencies due to new datasets from diverse populations and provides updated carrier frequencies based on the combined data from 184 352 genomes and exomes in gnomAD. We recommend a periodic review for inclusion of new population data to update carrier screening panels in the future.


Assuntos
Exoma , Variação Genética , Genes Recessivos , Genômica , Heterozigoto , Humanos
11.
Eur J Med Genet ; 65(6): 104520, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35568357

RESUMO

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016-2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.


Assuntos
Microcefalia , Transtornos do Neurodesenvolvimento , Exoma , Genes Recessivos , Humanos , Índia , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Linhagem , Sequenciamento Completo do Exoma
12.
Front Endocrinol (Lausanne) ; 13: 832911, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574020

RESUMO

Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the LEPR, PCSK1, POMC, MC3R and MC4R genes could reduce the societal burden and improve the clinical management of early severe childhood obesity and its implementation should be further investigated.


Assuntos
Obesidade Mórbida , Obesidade Pediátrica , Adolescente , Criança , Feminino , Genes Recessivos , Humanos , Recém-Nascido , Leptina/genética , Masculino , Melanocortinas/genética , Obesidade Mórbida/genética , Obesidade Pediátrica/genética , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética , Aumento de Peso
13.
J Peripher Nerv Syst ; 27(2): 100-112, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35383421

RESUMO

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features. METHODS: We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria. RESULTS: A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT-associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations. INTERPRETATION: This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.


Assuntos
Doença de Charcot-Marie-Tooth , África/epidemiologia , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Genes Recessivos , Humanos , Proteínas dos Microfilamentos/genética , Mutação , Fenótipo , Proteínas/genética
14.
Genet Med ; 24(7): 1523-1535, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35486108

RESUMO

PURPOSE: This study aimed to investigate the clinical and genetic aspects of solute carrier (SLC) genes in inherited retinal diseases (IRDs). METHODS: Exome sequencing data were filtered to identify pathogenic variants in SLC genes. Analysis of transcript and protein expression was performed on fibroblast cell lines and retinal sections. RESULTS: Comprehensive analysis of 433 SLC genes in 913 exome sequencing IRD samples revealed homozygous pathogenic variants in 6 SLC genes, including 2 candidate novel genes, which were 2 variants in SLC66A1, causing autosomal recessive retinitis pigmentosa (ARRP), and a variant in SLC39A12, causing autosomal recessive mild widespread retinal degeneration with marked macular involvement. In addition, we present 4 families with ARRP and homozygous null variants in SLC37A3 that were previously suggested to cause retinitis pigmentosa, 2 of which cause exon skipping. The recently reported SLC4A7- c.2007dup variant was found in 2 patients with ARRP resulting in the absence of protein. Finally, variants in SLC24A1 were found in 4 individuals with either ARRP or congenital stationary night blindness. CONCLUSION: We report on SLC66A1 and SLC39A12 as candidate novel IRD genes, establish SLC37A3 pathogenicity, and provide further evidence of SLC4A7 as IRD genes. We extend the phenotypic spectrum of SLC24A1 and suggest that its ARRP phenotype may be more common than previously reported.


Assuntos
Retinite Pigmentosa , Análise Mutacional de DNA/métodos , Genes Recessivos , Estudos de Associação Genética , Humanos , Mutação , Linhagem , Fenótipo , Retinite Pigmentosa/genética
15.
Hum Mutat ; 43(7): 877-881, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35446444

RESUMO

An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5' and 3' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5' and 3' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.


Assuntos
Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Sistemas CRISPR-Cas , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Epidermólise Bolhosa Distrófica/terapia , Genes Recessivos , Haplótipos , Humanos , Mutação
16.
Pediatr Dermatol ; 39(3): 420-424, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35412663

RESUMO

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) refers to non-syndromic ichthyosis caused by mutations in one of the 13 identified genes. There are limited data on the genotype of ARCI and its phenotypic correlation from India. OBJECTIVES: The aim of this study was to characterize the genotype of ARCI among patients from the Indian subcontinent. METHODS: Twenty-eight patients clinically diagnosed as ARCI were recruited prospectively from September 2017 to June 2019 (21 months). DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel. The variants identified were confirmed by Sanger sequencing and compared with known pathogenic variants to establish pathogenicity. We also attempted to correlate the phenotype with the genotype. RESULTS: Among the 28 patients recruited (M = 17, F = 11), we identified phenotypes of congenital ichthyosiform erythroderma in 12 (42.9%), 8 with lamellar ichthyosis (28.6%), 5 with intermediate phenotype (17.9%), and 3 with bathing suit ichthyosis (10.7%). Pathogenic and likely pathogenic variants were identified in 22 (78.6%) patients, involving 7 out of the 13 known ARCI genes while 6 (21.4%) did not have pathogenic variants. These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each. Previously unknown pathogenic variants were found in 59.1 % of patients. CONCLUSIONS: Our patients with ARCI were found to have genotypes as previously described in other populations.


Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Aciltransferases , Proteínas de Transporte de Ácido Graxo/genética , Genes Recessivos , Genótipo , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Lipase , Mutação , Fenótipo , Centros de Atenção Terciária
17.
Orphanet J Rare Dis ; 17(1): 97, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241111

RESUMO

BACKGROUND: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. RESULTS: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. CONCLUSION: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.


Assuntos
Artrite , Colágeno Tipo IX , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial , Osteocondrodisplasias , Descolamento Retiniano , Artrite/diagnóstico , Artrite/genética , Colágeno Tipo IX/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Genes Recessivos/genética , Perda Auditiva Neurossensorial/genética , Humanos , Mutação/genética , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética , Descolamento Retiniano/patologia
18.
Hum Mutat ; 43(7): 900-918, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35344616

RESUMO

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.


Assuntos
Anormalidades Craniofaciais , Nanismo , Deformidades Congênitas dos Membros , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Anormalidades Urogenitais , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Nanismo/diagnóstico , Nanismo/genética , Genes Recessivos , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Masculino , Fenótipo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(3): 321-324, 2022 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-35315045

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a pediatric patient suspected for Autosomal Recessive Congenital Ichthyosis (ARCI). METHODS: Clinical data of the patient was analyzed. Peripheral blood samples were collected from the patient and his parents for the extraction of genomic DNA. Next-generation sequencing (NGS) was then carried out. Candidate variants were confirmed by Sanger sequencing. A variety of bioinformatic tools including Mutation Taster, PROVEAN, and PolyPhen2 were used to predict the pathogenicity of the variants based on guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patient, a 1-month-and-7-day-old male, had presented with cutaneous erythema and fine scaling of the whole body. NGS revealed that he has harbored compound heterozygous variants c.1579G>A (p.Val527Met) (paternal) and c.923T>C (p.Leu308Pro) (maternal) of the ALOX12B gene. The former was known to be likely pathogenic, while the latter was unreported previously and categorized as "likely pathogenic" based on the ACMG guidelines. Based on the clinical and genetic findings, the patient was diagnosed with ARCI. CONCLUSION: The c.1579G>A and c.923T>C variants of the ALOX12B genes probably underlay the ARCI in this patient. Above finding has enriched the spectrum of ALOX12B mutations and enabled molecular diagnosis of the patient, based on which genetic counseling and prenatal diagnosis may be provided.


Assuntos
Ictiose Lamelar , Araquidonato 12-Lipoxigenase/genética , Criança , Feminino , Genes Recessivos , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ictiose Lamelar/genética , Masculino , Mutação , Gravidez
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