Prevalence Estimates of Predicted Pathogenic COL4A3 - COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome

Background: The prevalence of Alport syndrome varies from one in 5,000 to one in 53,000. This study estimated the frequencies of predicted pathogenic COL4A3- COL4A5 variants in sequencing databases of populations without known kidney disease. Methods: Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria that considered collagen IV α3-α5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3-COL4A5 variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants. Results:COL4A3-COL4A5 variants resulting in position 1 Gly substitutions were confirmed associated with haematuria (p each <0.0001). Predicted pathogenic COL4A5 variants were found in at least one in 2,320 individuals. p.(Gly624Asp), represented nearly half (16/33, 48%) the variants in Europeans. Most COL4A5 variants (54/59, 92%) had a biochemical feature that potentially mitigated clinical impact. Predicted pathogenic heterozygous COL4A3 and COL4A4 variants affected one in 106 of the population, consistent with the finding of Thin basement membrane nephropathy in normal donor kidney biopsies. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals and digenic variants in at least one in 44,793. Conclusions: The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3-COL4A5 variants but must be adjusted for the disease penetrance of individual variants, as well as the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.

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Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

Bioscience Reports ◽

10.1042/bsr20193443 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

Author(s):

Chunli Wei ◽

Ting Xiao ◽

Jingliang Cheng ◽

Jiewen Fu ◽

Qi Zhou ◽

...

Keyword(s):

Novel Mutation ◽

Gene Mutations ◽

Chinese Family ◽

Compound Heterozygous ◽

Missense Mutations ◽

The Novel ◽

Pathogenic Variants ◽

Pathogenic Genes ◽

Compound Heterozygous Variants ◽

Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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Clinical and Pathological Features of a Newborn With Compound Heterozygous ANKS6 Variants

Pediatric and Developmental Pathology ◽

10.1177/1093526619881541 ◽

2019 ◽

Vol 23 (3) ◽

pp. 235-239

Author(s):

Sakil Kulkarni ◽

Brooj Abro ◽

Maria Laura Duque Lasio ◽

Janis Stoll ◽

Dorothy K Grange ◽

...

Keyword(s):

Cardiac Failure ◽

Renal Dysplasia ◽

Cardiomyocyte Hypertrophy ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Genes Encoding ◽

Cystic Renal Dysplasia ◽

Cystic Renal Disease ◽

Compound Heterozygous Variants

We report a term female infant born to nonconsanguineous parents who presented with renal failure at birth, hypothyroidism, cholestasis, and progressive cardiac dysfunction. Multigene next-generation sequencing panels for cholestasis, cardiomyopathy, and cystic renal disease did not reveal a unifying diagnosis. Whole exome sequencing revealed compound heterozygous pathogenic variants in ANKS6 (Ankyrin Repeat and Sterile Alpha Motif Domain Containing 6), which encodes a protein that interacts with other proteins of the Inv compartment of cilium ( NEK8, NPHP2/INVS, and NPHP3). ANKS6 has been shown to be important for early renal development and cardiac looping in animal models. Autopsy revealed cystic renal dysplasia and cardiomyocyte hypertrophy, disarray, and focal necrosis. Liver histology revealed cholestasis and centrilobular necrosis, which was likely a result of progressive cardiac failure. This is the first report of compound heterozygous variants in ANKS6 leading to a nephronopthisis-related ciliopathy-like phenotype. We conclude that pathogenic variants in ANKS6 may present early in life with severe renal and cardiac failure, similar to subjects with variants in genes encoding other proteins in the Inv compartment of the cilium.

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Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy

Neurology Genetics ◽

10.1212/nxg.0000000000000505 ◽

2020 ◽

Vol 6 (5) ◽

pp. e505

Author(s):

Rodrigo de Holanda Mendonça ◽

Ciro Matsui ◽

Graziela Jorge Polido ◽

André Macedo Serafim Silva ◽

Leslie Kulikowski ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Copy Number ◽

Clinical Phenotype ◽

Muscular Atrophy ◽

Large Population ◽

Survival Motor Neuron ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Exon 1 ◽

Compound Heterozygous Variants

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

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Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

Journal of Ophthalmology ◽

10.1155/2021/6684045 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Qin Xiang ◽

Yanna Cao ◽

Hongbo Xu ◽

Zhijian Yang ◽

Liang Tang ◽

...

Keyword(s):

Family Members ◽

Major Facilitator Superfamily ◽

Chinese Family ◽

Macular Dystrophy ◽

Compound Heterozygous ◽

The Novel ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Major Facilitator ◽

Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

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Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1241-z ◽

2019 ◽

Vol 14 (1) ◽

Author(s):

Niu Li ◽

Yufei Xu ◽

Yi Zhang ◽

Guoqiang Li ◽

Tingting Yu ◽

...

Keyword(s):

Postnatal Growth ◽

Compound Heterozygous ◽

Loss Of Function ◽

Atrioventricular Canal ◽

Multiple Systems ◽

Feeding Difficulties ◽

Functional Studies ◽

Pathogenic Variants ◽

Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

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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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Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

npj Genomic Medicine ◽

10.1038/s41525-021-00173-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Hosneara Akter ◽

Mohammad Shahnoor Hossain ◽

Nushrat Jahan Dity ◽

Md. Atikur Rahaman ◽

K. M. Furkan Uddin ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Diseases ◽

Leigh Syndrome ◽

Genetic Profile ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Rare Genetic Diseases ◽

Compound Heterozygous Variants

AbstractCollectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet–Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.

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Different Phenotypes in Pseudodominant Inherited Retinal Dystrophies

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.625560 ◽

2021 ◽

Vol 9 ◽

Author(s):

Imen Habibi ◽

Yosra Falfoul ◽

Hoai Viet Tran ◽

Khaled El Matri ◽

Ahmed Chebil ◽

...

Keyword(s):

Index Patient ◽

Pathogenic Variant ◽

Compound Heterozygous ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Subretinal Fibrosis ◽

Precise Diagnosis ◽

Compound Heterozygous Variants ◽

Successive Generations

Retinal dystrophies (RD) are a group of Mendelian disorders caused by rare genetic variations leading to blindness. A pathogenic variant may manifest in both dominant or recessive mode and clinical and genetic heterogeneity makes it difficult to establish a precise diagnosis. In this study, families with autosomal dominant RD in successive generations were identified, and we aimed to determine the disease's molecular origin in these consanguineous families. Whole exome sequencing was performed in the index patient of each family. The aim was to determine whether these cases truly represented examples of dominantly inherited RD, or whether another mode of inheritance might be applicable. Six potentially pathogenic variants in four genes were identified in four families. In index patient with enhanced S-cone syndrome in F1, we identified a new digenetic combination: a heterozygous variant p.[G51A];[=] in RHO and a homozygous pathogenic variant p.[R311Q];[R311Q] in NR2E3. Helicoid subretinal fibrosis associated with recessive NR2E3 variant p.[R311Q];[R311Q] was identified in F2. A new frameshift variant c.[105delG];[105delG] in RDH12 was found in F3 with cone-rod dystrophy. In F4, the compound heterozygous variants p.[R964*];[W758*] were observed in IMPG2 with a retinitis pigmentosa (RP) phenotype. We showed that both affected parents and the offspring, were homozygous for the same variants in all four families. Our results provide evidence that in consanguineous families, autosomal recessive can be transmitted as pseudodominant inheritance in RD patients, and further extend our knowledge of pathogenic variants in RD genes.

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DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease

PLoS ONE ◽

10.1371/journal.pone.0252786 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252786

Author(s):

Hong Xia ◽

Xiangjun Huang ◽

Sheng Deng ◽

Hongbo Xu ◽

Yan Yang ◽

...

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Exome Sequencing ◽

Sanger Sequencing ◽

Congenital Heart ◽

Chinese Family ◽

Compound Heterozygous ◽

Internal Organs ◽

Pathogenic Variants ◽

Compound Heterozygous Variants

Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family.

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Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency

Frontiers in Genetics ◽

10.3389/fgene.2021.651878 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qi Tian ◽

Yang Cao ◽

Li Shu ◽

Yongjun Chen ◽

Ying Peng ◽

...

Keyword(s):

Brain Mri ◽

Genetic Diagnosis ◽

Clinical Information ◽

Molybdenum Cofactor ◽

Compound Heterozygous ◽

Causative Gene ◽

Pathogenic Variants ◽

First Case ◽

Healthy Family ◽

Compound Heterozygous Variants

Background: The molybdenum cofactor (Moco) deficiency in humans results in the inactivity of molybdenum-dependent enzymes and is caused by pathogenic variants in MOCS1 (Molybdenum cofactor synthesis 1), MOCS2 (Molybdenum cofactor synthesis 2), and GPHN (Gephyrin). These genes along with MOCS3 (Molybdenum cofactor synthesis 3) are involved in Moco biosynthesis and providing cofactors to Moco-dependent enzymes. Until now, there was no study to confirm that MOCS3 is a causative gene of Moco deficiency.Methods: Detailed clinical information was collected in the pedigree. The Whole-exome sequencing (WES) accompanied with Sanger sequencing validation were performed.Results: We described the clinical presentations of an infant, born to a non-consanguineous healthy family, diagnosed as having MOCS3 variants caused Moco deficiency and showing typical features of Moco deficiency including severe neurologic symptoms and cystic encephalomalacia in the brain MRI, resulting in neonatal death. Compound heterozygous variants in the MOCS3 gene were identified by WES. Positive sulfite and decreased levels of uric acid in plasma and urine were detected.Conclusion: To our knowledge, this is the first case of MOCS3 variants causing Moco deficiency. Our study may contribute to genetic diagnosis of Moco deficiency and future genetic counseling.

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