Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form

2021 ◽  
Vol 14 (1) ◽  
pp. e236732
Author(s):  
Weiyi Mu ◽  
Teresa Heller ◽  
Kristin W Barañano
Keyword(s):  
Autosomal Recessive ◽  
Phenotypic Variability ◽  
Compound Heterozygous ◽  
Pontocerebellar Hypoplasia ◽  
Neurocognitive Impairments ◽  
Pathogenic Variants ◽  
Novel Variant ◽  
A Subunit ◽  
Rna Exosome ◽  
Exosome Complex

Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype–phenotype associations.

scholarly journals Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

2022 ◽  
Author(s):  
Zhidan Hong ◽  
Xuanyi He ◽  
Fang Yu ◽  
Huanyu Liu ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Pathological Examination ◽  
Compound Heterozygous ◽  
Over Expression ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
Novel Variant ◽  
Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

scholarly journals Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

Genetics ◽  
2016 ◽  
Vol 205 (1) ◽  
pp. 221-237 ◽  
Author(s):  
Milo B. Fasken ◽  
Jillian S. Losh ◽  
Sara W. Leung ◽  
Sergine Brutus ◽  
Brittany Avin ◽  
...  
Keyword(s):  
Pontocerebellar Hypoplasia ◽  
Disease Mutations ◽  
Rna Exosome ◽  
Insight Into ◽  
Exosome Complex

scholarly journals Spondyloocular Syndrome: A Novel XYLT2 Variant with Description of the Neonatal Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriella Doddato ◽  
Alessandra Fabbiani ◽  
Chiara Fallerini ◽  
Mirella Bruttini ◽  
Theodora Hadjistilianou ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Phenotypic Variability ◽  
Autosomal Recessive Inheritance ◽  
Nuchal Translucency ◽  
Gene Encoding ◽  
Nasal Bridge ◽  
Facial Profile ◽  
Pathogenic Variants ◽  
Skeletal Defects ◽  
Bone Abnormalities

Spondyloocular syndrome (SOS) is a skeletal disorder caused by pathogenic variants in XYLT2 gene encoding a xylotransferase involved in the biosynthesis of proteoglycans. This condition, with autosomal recessive inheritance, has a high phenotypic variability. It is characterized by bone abnormalities (osteoporosis, fractures), eye and cardiac defects, hearing impairment, and varying degrees of developmental delay. Until now only 20 mutated individuals have been reported worldwide. Here, we describe two siblings from consanguineous healthy parents in which a novel homozygous frameshift variant c.1586dup p(Thr530Hisfs*) in the XYLT2 gene was detected by exome sequencing (ES). The first patient (9 years) presented short stature with skeletal defects, long face, hearing loss and cataract. The second patient, evaluated at a few days of life, showed macrosomia, diffuse hypertrichosis on the back, overabundant skin in the retronucal area, flattened facial profile with drooping cheeks, elongated eyelid rims, wide and flattened nasal bridge and turned down corners of the mouth. During the prenatal period, high nuchal translucency and intestinal hyperechogenicity were observed at ultrasound. In conclusion, these two siblings with a novel pathogenic variant in XYLT2 further expand the clinical and mutational spectrum of SOS.

scholarly journals Audiological features in Serbian patients with hearing impairment identified with c.35delG in the GJB2 gene

2021 ◽  
pp. 98-98
Author(s):  
Bojana Dobric ◽  
Danijela Radivojevic ◽  
Jovana Jecmenica ◽  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Environmental Causes ◽  
35Delg Mutation

Introduction/Objective. Hearing impairment (HI) is the most common sensorineural disorder with an incidence of 1/700-1000 newborns. Variants in the GJB2 gene are the major cause of autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL). The degree of HI in patients with detected mutations in GJB2 gene ranges from mild to profound. The aim of this study was to determine possible genotype-phenotype association between audiometric characteristics and detected genotypes in ARNSHL patients from Serbia. Methods. Ninety-two patients with ARNSHL underwent genetic analysis with PCR-ARMS and sequencing of the GJB2 gene. Audiological analyses were obtained in all patients using a combination of several methods to estimate the degree of hearing loss. Results. Audiological analysis performed in the 92 probands showed moderate to profound range of hearing loss. All identified pathogenic variants accounted for 42.39% of the mutant alleles (78/184 alleles), with the c.35delG mutation being the most frequent (30.43%). Genotype-phenotype correlation in an isolated group of 37 patients bearing c.35delG in the homozygous, compound heterozygous or heterozygous state. In this group the majority of patients (30/37, 81.08%) exhibited severe to profound hearing deficit. Conclusion. Association between genotype and the degree of hearing impairment in patients analyzed in this study demonstrated that patients with bi-allelic truncating mutations i.e. c.35delG, associate with the more severe hearing loss when compared with those identified with only one affected allele. The various degrees of hearing impairment observed in heterozygous patients could be explained by the presence of an undetected second mutation or other modifier genes or environmental causes.

scholarly journals The genetic basis of classical galactosaemia in Polish patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Aleksandra Jezela-Stanek ◽  
Anna Bauer ◽  
Katarzyna Wertheim-Tysarowska ◽  
Jerzy Bal ◽  
Agnieszka Magdalena Rygiel ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Basis ◽  
Dna Analysis ◽  
Current Knowledge ◽  
Autosomal Recessive Disorder ◽  
Molecular Characteristics ◽  
Compound Heterozygous ◽  
Classic Galactosemia ◽  
Pathogenic Variants ◽  
Molecular Etiology

AbstractClassic galactosemia (OMIM #230400) is an autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13. Its diagnosis is established by detecting elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity. Biallelic pathogenic variants in the GALT gene is confirmed by DNA analysis. Our paper presents molecular characteristics of 195 Polish patients diagnosed with galactosemia I, intending to expand the current knowledge of this rare disease's molecular etiology. To the best of our knowledge, the described cohort of galactosemia patients is the largest single-center cohort presented so far.

scholarly journals Spectrum of MEFV Variants and Genotypes among Clinically Diagnosed FMF Patients from Southern Lebanon

2020 ◽  
Vol 8 (3) ◽  
pp. 35
Author(s):  
Ali El Roz ◽  
Ghassan Ghssein ◽  
Batoul Khalaf ◽  
Taher Fardoun ◽  
José-Noel Ibrahim
Keyword(s):  
Autosomal Recessive ◽  
Mefv Gene ◽  
Allele Frequencies ◽  
Molecular Testing ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
South Lebanon ◽  
Auto Inflammatory Disease ◽  
Mediterranean Fever ◽  
The Mean

Background: Familial Mediterranean Fever (FMF) is an autosomal recessive auto-inflammatory disease characterized by pathogenic variants in the MEFV gene, with allele frequencies greatly varying between countries, populations and ethnic groups. Materials and methods: In order to analyze the spectrum of MEFV variants and genotypes among clinically diagnosed FMF patients from South Lebanon, data were collected from 332 participants and 23 MEFV variants were screened using a Real-Time PCR Kit. Results: The mean age at symptom onset was 17.31 ± 13.82 years. The most prevalent symptoms were abdominal pain, fever and myalgia. MEFV molecular analysis showed that 111 patients (63.79%) were heterozygous, 16 (9.20%) were homozygous, and 47 (27.01%) carried two variants or more. E148Q was the most encountered variant among heterozygous subjects. E148Q/M694V was the most frequent in the compound heterozygous/complex genotype group, while M694I was the most common among homozygous patients. Regarding allele frequencies, M694V was the most common variant (20.7%), followed by E148Q (17.1%), V726A (15.7%) and M694I (13.2%). Conclusion: The high percentage of heterozygous patients clinically diagnosed as FMF highlights the pseudo-dominant transmission of the disease in Lebanon and emphasizes the importance of molecular testing for a more accurate diagnosis and better management and treatment of FMF.

scholarly journals MCAD deficiency caused by compound heterozygous pathogenic variants in ACADM

2022 ◽  
Vol 9 (1) ◽  
Author(s):  
Fumikatsu Nohara ◽  
Go Tajima ◽  
Hideo Sasai ◽  
Yoshio Makita
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Residual Activity ◽  
Complete Loss ◽  
Compound Heterozygous ◽  
Limit Of Quantification ◽  
Mcad Deficiency ◽  
Pathogenic Variants ◽  
Chain Acyl ◽  
Acyl Coenzyme A

AbstractMedium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disease caused by biallelic pathogenic ACADM variants. We report a case of an asymptomatic Japanese girl with MCAD deficiency caused by compound heterozygous pathogenic variants (NM_000016.5:c.1040G > T (p.Gly347Val) and c.449_452delCTGA (p.Thr150ArgfsTer4)). Because the MCAD residual activity in lymphocytes of the patient was below the limit of quantification, both variants are likely to cause complete loss of MCAD enzymatic activity.

scholarly journals Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1508
Author(s):  
Isabelle Jéru ◽  
Amira Nabil ◽  
Gehad El-Makkawy ◽  
Olivier Lascols ◽  
Corinne Vigouroux ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Genetic Disorders ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Partial Lipodystrophy ◽  
Mandibular Hypoplasia ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

scholarly journals Three Patients With Disseminated Mycobacterial Infections Due to Severe Defects in Interferon Gamma Receptor Signaling: A Challenging Diagnosis

2021 ◽  
Author(s):  
Zijun Zhou ◽  
Iris H.I.M. Hollink ◽  
Arjan Bouman ◽  
Mirthe S. Lourens ◽  
Rik A. Brooimans ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Compound Heterozygous ◽  
Mycobacterial Infections ◽  
Susceptibility To Infection ◽  
Gamma Receptor ◽  
Alu Insertion ◽  
Whole Exome ◽  
Novel Variant ◽  
Ifn Γ

Abstract IFN–gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium , M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN–α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.

scholarly journals Genetics of alkaptonuria – an overview

2015 ◽  
Vol 62 (s11) ◽  
pp. 27-32
Author(s):  
Andrea Zatkova ◽  
Martina Nemethova
Keyword(s):  
Inborn Error ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Homogentisic Acid ◽  
Compound Heterozygous ◽  
Ochronotic Arthropathy ◽  
Pathogenic Variants ◽  
Gene Coding ◽  
Metabolic Block ◽  
Rare Autosomal Recessive Disease

Abstract Alkaptonuria (AKU) is the first described inborn error of metabolism and a classical example of rare autosomal recessive disease. AKU patients carry homozygous or compound heterozygous mutations of the gene coding for enzyme homogentisate dioxygenase (HGD) involved in metabolism of tyrosine. The metabolic block in AKU causes accumulation of homogentisic acid (HGA) that, with advancing age of the patient, leads to severe and painful ochronotic arthropathy. HGD gene was mapped to chromosome 3q13.3 and is composed of 14 exons. In about 400 patients, 142 pathogenic variants were reported that are listed in HGD mutations database (http://hgddatabase.cvtisr.sk/). In this review, we summarise different aspects of AKU genetics and impact of the HGD variants on enzyme function.

Sign in / Sign up

Export Citation Format

Share Document