Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study

Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched.Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively.Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The “recurrent variants” included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection.Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.

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A novel LOXHD1 variant in a Chinese couple with hearing loss

Journal of International Medical Research ◽

10.1177/0300060519884197 ◽

2019 ◽

Vol 47 (12) ◽

pp. 6082-6090 ◽

Cited By ~ 1

Author(s):

Chuan Zhang ◽

Shengju Hao ◽

Yali Liu ◽

Bingbo Zhou ◽

Furong Liu ◽

...

Keyword(s):

Hearing Loss ◽

Molecular Diagnosis ◽

Protein Function ◽

Mexican American ◽

Compound Heterozygous ◽

Congenital Hearing Loss ◽

Targeted Next Generation Sequencing ◽

Novel Variants ◽

Novel Variant ◽

Compound Heterozygous Variants

Objective To perform molecular diagnosis and genetic counseling in a young Chinese couple with congenital hearing loss. Methods Variant screening analysis was performed by PCR and direct Sanger sequencing or targeted next-generation sequencing of all known hearing loss genes. Novel variants were evaluated by PolyPhen2 and PROVEAN software tools to evaluate possible effects on protein function. Results We identified causative variants in the young couple: c.235delC (rs80338943)/c.299-300delAT (rs111033204) compound heterozygous variants of GJB2 in the husband and c.1828G>A (p.Glu610Lys, rs535637788)/c.2825-2827delAGA compound heterozygous variants of LOXHD1 in the wife. The LOXHD1 c.1828G>A variant has only previously been reported in a Mexican-American individual in the 1000 Genomes Project database. Using PolyPhen2 and PROVEAN, we speculated that the LOXHD1 variant c.1828G>A is potentially pathogenic. Conclusion We carried out molecular diagnosis in a young couple with congenital hearing loss, and identified different disease-causing genes in the two individuals. The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. We determined this to be a potential pathogenic variant, and a novel variant associated with hearing loss in a Chinese individual.

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Identification of the rare compound heterozygous variants in the NEB gene in a Korean family with intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness

Journal of Human Genetics ◽

10.1038/jhg.2014.87 ◽

2014 ◽

Vol 59 (12) ◽

pp. 643-647 ◽

Cited By ~ 5

Author(s):

Hyun-Seok Jin ◽

Jong-Bin Lee ◽

Kyung Kim ◽

Ki-Young Lee ◽

Vit-Na Choi ◽

...

Keyword(s):

Early Childhood ◽

Intellectual Disability ◽

Muscle Weakness ◽

Compound Heterozygous ◽

Childhood Onset ◽

Korean Family ◽

Compound Heterozygous Variants

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Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-310958 ◽

2017 ◽

Vol 102 (2) ◽

pp. 276-281 ◽

Cited By ~ 4

Author(s):

Sonika Rathi ◽

Subhadra Jalali ◽

Ganeswara Rao Musada ◽

Satish Patnaik ◽

Divya Balakrishnan ◽

...

Keyword(s):

Retinopathy Of Prematurity ◽

Clinical Manifestations ◽

Study Cohort ◽

Compound Heterozygous ◽

Low Frequencies ◽

Indian Patients ◽

Intron 1 ◽

Heterozygous Variant ◽

Novel Variants ◽

Preterm Babies

AimRetinopathy of prematurity (ROP) is a vasoproliferative eye disease in preterm infants. Based on its phenotypic similarities with familial exudative vitreo retinopathy (FEVR), the present study was conducted to screen the Norrin signalling pathway genes (already been implicated in FEVR) for understanding their involvement among Indian patients with ROP.MethodsThe study cohort consisted of patients with ROP (n=246) and controls (n=300) that included full term (n=110) and preterm babies devoid of ROP (n=190). Screening of the NDP, FZD4, TSPAN12 genes were accomplished by resequencing the entire coding and untranslated regions (UTR). The genotype data of the patients with ROP were analysed in the background of their clinical manifestations and further analysed in conjunction with other available data on these genes worldwide.ResultsTwo novel variants in intron 1 (IVS1 +16A>G) and 3′UTR (c.5 22T>C) along with a previously reported change in the 5′UTR (c.395_409del14bp) were observed in the NDP gene in three patients with ROP. Screening of the FZD4 revealed four heterozygous variants, p.(Pro33Ser), p.(Pro168Ser), p.(Ile192Ile) and p.(Ile360Val), a compound heterozygous (p.(Pro33Ser)/p.(Pro168Ser)) and a 3′UTR (c*G>T) variants in the study cohort. Variants p.(Pro33Ser) and p.(Pro168Ser) were found to be significantly associated with ROP. A heterozygous variant p.(Leu119Arg) in TSPAN12 gene was observed in a patient with threshold ROP. However, a formal genotype–phenotype correlation could not be established due to the low frequencies of the variant alleles in these genes.ConclusionsThis is a first study that revealed association of few variants in Norrin signalling genes among Indian patients with ROP that warrants further detailed investigation worldwide.

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Recurrent respiratory viral diseases and chronic sequelae due to dominant negative IFIH1

10.1101/2020.07.01.20105379 ◽

2020 ◽

Author(s):

Christin L Deal ◽

Timothy J Thauland ◽

Rebecca Signer ◽

Stanley F Nelson ◽

Hane Lee ◽

...

Keyword(s):

Viral Infections ◽

Respiratory Infections ◽

Clinical Manifestations ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Compound Heterozygous ◽

Loss Of Function ◽

Negative Effect ◽

Respiratory Viral Infections ◽

Compound Heterozygous Variants

Viral respiratory infections are the most common childhood infection worldwide. However, even common pathogens can have significant consequences in the context of patients with primary immunodeficiency diseases. More than half or viral infections annually are due to rhinovirus/enterovirus strains. Most clinical manifestations of viral infection are mild. However 3% of cases result in hospitalization in patients who have no other known risk factors. These patients may have an inborn error of immunity, a genetic susceptibility to viral infections. Here we present the case of an adult male who suffered respiratory viral infections his whole life and developed chronic, inflammatory damage to sinuses and lungs as a consequence. Genomic sequencing identified compound heterozygous variants in the IFIH1 gene, encoding the protein Melanoma Differentiation Association Protein 5 (MDA5), a RIG-I-like cytoplasmic sensor of RNA intracellular infections. We show a dominant negative effect on these variants on the level of interferon-induced expression of MDA5 protein. This work supports that loss-of-function variants in IFIH1 affect the sensing of viral infections. Underlying genomic variants may dictate the point at which recurrent, respiratory viral infections leave commonplace experience and incur lasting damage.

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Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2021/9957712 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Xiao-Hui Wang ◽

Le Xie ◽

Sen Chen ◽

Kai Xu ◽

Xue Bai ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Bioinformatics Analysis ◽

Compound Heterozygous ◽

Congenital Deafness ◽

Chinese Families ◽

Novel Variants ◽

Common Causes ◽

Compound Heterozygous Variants ◽

Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

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Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01600-8 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Aliaa H. Abdelhakim ◽

Avinash V. Dharmadhikari ◽

Sara D. Ragi ◽

Jose Ronaldo Lima de Carvalho ◽

Christine L. Xu ◽

...

Keyword(s):

Coenzyme Q ◽

Clinical Manifestations ◽

Missense Variant ◽

Neurological Involvement ◽

Cone Dystrophy ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Compound Heterozygous Variants ◽

End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

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Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics

Pancreatology ◽

10.1016/j.pan.2020.01.007 ◽

2020 ◽

Vol 20 (3) ◽

pp. 562-568 ◽

Cited By ~ 1

Author(s):

Shu Liu ◽

Zhiqing Wang ◽

Jianhui Jiang ◽

Xianqiong Luo ◽

Qingshan Hong ◽

...

Keyword(s):

Molecular Genetics ◽

Clinical Manifestations ◽

Compound Heterozygous ◽

Imaging Findings ◽

Compound Heterozygous Variants

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Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2

Human Genome Variation ◽

10.1038/s41439-020-00119-5 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Shoko Ikeda ◽

Chika Akamatsu ◽

Akifumi Ijuin ◽

Ami Nagashima ◽

Megumi Sasaki ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Genetic Analysis ◽

Airway Obstruction ◽

Renal Agenesis ◽

Recurrence Risk ◽

Compound Heterozygous ◽

Fraser Syndrome ◽

Novel Variants ◽

Compound Heterozygous Variants

AbstractFraser syndrome (FS) involves multiple malformations and has a 25% recurrence risk among siblings. However, these malformations are difficult to detect prenatally, hampering prenatal diagnosis. Here, we describe a fetus with FS diagnosed using ultrasonography. Ultrasonography revealed congenital high airway obstruction syndrome and renal agenesis. Syndactyly of both hands and cryptophthalmos were noted postnatally, and the diagnosis was confirmed by genetic analysis, which showed novel compound heterozygous variants of FREM2.

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POLR3A-related hypomyelinating leukodystrophy: case report and literature review

Neuromuscular Diseases ◽

10.17650/2222-8721-2021-11-4-48-54 ◽

2020 ◽

Vol 11 (4) ◽

pp. 48-54

Author(s):

A. F. Murtazina ◽

T. V. Markova ◽

A. A. Orlova ◽

O. P. Ryzhkova ◽

O. A. Shchagina ◽

...

Keyword(s):

Case Report ◽

Hypogonadotropic Hypogonadism ◽

Molecular Genetic ◽

Clinical Manifestations ◽

Brain Magnetic Resonance Imaging ◽

Permanent Teeth ◽

Diagnostic Process ◽

Compound Heterozygous ◽

Compound Heterozygous Variants ◽

First Year Of Life

Hypomyelinating leukodystrophies (HL) is a group of genetically heterogeneous neurodegenerative disorders characterized by a lack of brain myelin deposition. One of the most common autosomal recessive HL is HL type 7 caused by mutations in the POLR3A gene. We reported the first clinical case of a Russian patient with HL type 7.Proband is a 7‑year‑old patient with HL type 7. The diagnosis was confirmed by genealogy, neurological examination, brain magnetic resonance imaging and molecular genetic testing. Two compound‑heterozygous variants in the POLR3A gene were revealed in the patient. Each variant was described earlier in patients with variable clinical manifestations of neurodegenerative diseases. The peculiarities of clinical manifestations in our patient were the manifestation of the disease in the first year of life, the predominance of cerebellar symptoms, a movement limitation of the jaw, leading to worsening of dysarthria, a delay in the formation of permanent teeth and short stature. The course of the disease was moderate that could be explained by different effect of the variants in the POLR3A gene.POLR3A‑related disease is a group of clinically heterogeneous disorders manifesting from early childhood to adulthood and characterized by isolated spastic ataxia or ataxia combined with oligodontia and hypogonadotropic hypogonadism, isolated or complicated spastic paraplegia, as well as a combination of ataxia with extrapyramidal symptoms. Our case report demonstrates the complexity of diagnostic process in the absence of a peculiar clinical picture and specific changes in brain imaging.

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