P0065DOUBLE MUTATION INHERITANCE IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ALPORT SUNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jingyuan Xie
Keyword(s):  
Genetic Analysis ◽  
Focal Segmental Glomerulosclerosis ◽  
Clinical Symptoms ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Digenic Inheritance ◽  
Segmental Glomerulosclerosis ◽  
Whole Exome ◽  
The Family ◽  
Genetic Pools

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are the leading causes of ESRD globally. FSGS and AS are clinically heterogeneous nephropathies and mainly genetic causes are the mutations in genes expressed in podocytes and glomerular basement membrane (GBM) respectively. A simple Mendelian model fail to explain the genetic control of both nephropathies completely because of the heterogeneous nature and presence of incomplete penetrance. Therefore, here we investigated the possible digenic control of FSGS and AS. Method To detect the double mutational (mono- or di-genic) cause of FSGS and AS, we conducted whole exome sequencing (WES) and panel sequencing in 67 kidney patients during the period of four years (2015 to June 2019). Inclusion criteria was the proband's clinical symptoms confirming the FSGS or AS based on clinical symptoms and renal biopsy. Clinical and genetic analyses were implemented to correlate the phenotypes with genotypes. Results Genetic analysis discovered that 35 out of 67 (52.23%) had genetic cause of selected nephropathies and 24 out of 35 (68.57%) had mutations in COL4A (3,4 & 5) genes and 11 (31.42%) in other genes. Interestingly, we found 7 out of 35 patients (20%) with double mutations (mono- or di-genic) in COL4A3/COL4A4 genes. After the mentioned period, during routine genetic screening, we also found another patient having double mutations in COL4A3 gene. Subsequently, Sanger sequencing confirmed that the identified mutations were co-segregating with the disease(s) in an incomplete penetrance fashion within the family. Lastly, we found 16 mutations in 8 patients having either monogenic or digeneic double mutations in COL4A3 and/or COL4A4 genes. In sum, we found 12 (75%) mutations in COL4A3 and 4 in COL4A4 (25%), and5 probands (62.5%) had compound heterozygous mutations in COL4A3, 1 proband (12.5%) had in COL4A4 and 2 probands (25%) had digenic (COL4A3/COL4A4) mutations. Last of all, among all the mutations, 10 were novel and 6 have been described previously. Conclusion This genetic analysis provides the first evidence for digenic inheritance of FSGS. The nephrologists and clinical geneticists should keep this possibility in mind for the accuracy in diagnosis, disease management and genetic counseling in future. Additionally, we are also adding 10 novel mutations in COL4A3 and COL4A4 genetic pools.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

scholarly journals Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

2009 ◽  
Vol 168 (11) ◽  
pp. 1291-1304 ◽  
Author(s):  
M. M. Löwik ◽  
P. J. Groenen ◽  
E. N. Levtchenko ◽  
L. A. Monnens ◽  
L. P. van den Heuvel
Keyword(s):  
Genetic Analysis ◽  
Focal Segmental Glomerulosclerosis ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Segmental Glomerulosclerosis

APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries

2018 ◽  
Vol 34 (11) ◽  
pp. 1885-1893 ◽  
Author(s):  
Olivier Gribouval ◽  
Olivia Boyer ◽  
Bertrand Knebelmann ◽  
Alexandre Karras ◽  
Jacques Dantal ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Focal Segmental Glomerulosclerosis ◽  
West Indies ◽  
African Ancestry ◽  
Compound Heterozygous ◽  
French West Indies ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Segmental Glomerulosclerosis ◽  
Risk Variants

Abstract Background Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes. Methods In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes. Results The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02). Conclusions The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes.

Digenic Inheritance in Juvenile Open-Angle Glaucoma

2021 ◽  
Author(s):  
Bindu I. Somarajan ◽  
Shikha Gupta ◽  
Karthikeyan Mahalingam ◽  
Kishan Azmira ◽  
Viney Gupta
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Dominant ◽  
Open Angle Glaucoma ◽  
Open Angle ◽  
Northern India ◽  
Digenic Inheritance ◽  
Whole Exome ◽  
The Family ◽  
Primary Glaucoma ◽  
Study Participants

AbstractJuvenile open-angle glaucoma (JOAG) is an uncommon subset of primary glaucoma with an onset before the age of 40 years. In this case report, we describe the cosegregation of MYOC, p.Pro370Leu and LTBP2, p.Pro432Leu mutations in a family with JOAG. The family with autosomal dominant JOAG belonged to Northern India. The samples of proband and her parents were evaluated by whole exome sequencing. Sanger sequencing was conducted in all the study participants to check the mutations identified. Both MYOC and LTBP2 mutations were found to cosegregate in affected individuals leading to a severe JOAG phenotype, thereby suggesting a digenic inheritance of MYOC with LTBP2 in this family.

scholarly journals Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Véronique Taché ◽  
Liga Bivina ◽  
Sophie White ◽  
Jeffrey Gregg ◽  
Joshua Deignan ◽  
...  
Keyword(s):  
Lactic Acidosis ◽  
Neonatal Death ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Suspected Sepsis ◽  
Whole Exome ◽  
The Family ◽  
Biochemical Analyses ◽  
Male Neonate

A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1)gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due toLIPT1mutations, an underrecognized and underreported cause of neonatal death.Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases.

scholarly journals New PTEN mutation identified in a patient with rare bilateral choroidal ganglioneuroma

2020 ◽  
Author(s):  
Zhaoxin Jiang ◽  
Ting Zhang ◽  
Chonglin Chen ◽  
Limei Sun ◽  
Songshan Li ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
De Novo ◽  
Family Members ◽  
Genetic Alterations ◽  
Unrelated Control ◽  
Pten Mutation ◽  
Whole Exome ◽  
The Family ◽  
Multiple Abnormalities ◽  
Human Genome Reference

Abstract Background: Choroidal ganglioneuroma is an extremely rare tumor, and there is little knowledge regarding its pathogenesis. We aimed to investigate the phenotypic and genetic alterations in one sporadic patient with a rare case of bilateral choroidal ganglioneuroma. Methods: A 6-year-old boy with histological diagnosis of bilateral ganglioneuroma was recruited for the study. Comprehensive ophthalmic examinations were performed. Genomic DNA was extracted from the peripheral blood samples collected from the patient, his unaffected family members, and 200 unrelated control subjects from the same population. Whole exome sequencing was performed and raw reads were aligned to the human genome reference (hg19) using Burrows-Wheeler Aligner. DNA from all available family members was Sanger sequenced for segregation analysis. Results: Extensive bilateral retinal detachments were observed via optical coherence tomography. Diffuse thickening of choroid was identified with ultrasound B scan and magnetic resonance imaging. Genetic analysis revealed the presence of a novel heterozygous PTEN frameshift mutation, c.498delA (p.Thr167LeufsTer16), in exon 6. It was present in the affected individual, but not in any of the family members. Genetic analysis revealed that there was no mutation in neurofibromatosis-related genes in the family. Upon performing comprehensive systemic examinations, no obvious abnormalities in other organs were observed. Conclusions: A novel de novo PTEN mutation was identified in a patient with bilateral choroidal ganglioneuroma. Although PTEN mutations are known to induce multiple abnormalities, choroidal ganglioneuroma can be the first manifestation without abnormalities in other organs. Further studies are needed to confirm the association between choroidal ganglioneuroma and PTEN mutation.

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.

A Novel Missense Mutation in NALCN cause CLIFAHDD Syndrome and Prenatal Diagnosis in China

2020 ◽  
Author(s):  
Yuping Li ◽  
Chenglong Zhou ◽  
Yangran Chen ◽  
Haihong Shi ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Bioinformatics Analysis ◽  
Clinical Symptoms ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Foot Deformities ◽  
Gene Diagnosis ◽  
Rare Mutations ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant

Abstract Background : CLIFAHDD is caused by mutation in NALCN and characterized by facial malformation, hypotonia, and developmental delay. Recently rare mutations in NALCN associated with of CLIFAHDD syndrome have been reported. Methods : Whole exome sequencing (WES) was applied to a diagnosis suspected CLIFAHDD syndrome proband based on clinical symptoms. Blood samples were taken from the parents of the proband for co-segregation analysis using Sanger sequencing. In addition, prenatal gene diagnosis was performed to the family. Finally bioinformatics analysis was utilized to predict the pathogenesis of novel variant. Result : We reported a 24-hour-old proband with a novel missense variant c.3016G>T (p.Val1006Phe) in NALCN by WES. The proband showed clinical symptoms of head abnormalities, neck shortage, thumbs adduction, positional foot deformities and elbows contracture. Prenatal diagnosis revealed that the proband’s sibling did not carry c.3016G>T. Conclusion : Our findings indicate c.3016G>T is a novel pathogenic mutation, while extending new phenotype CLIFAHDD syndrome and enriching the mutation spectrum of the NALCN gene.

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