Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19

Abstract Introduction Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19. MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.

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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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Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Neurology Genetics ◽

10.1212/nxg.0000000000000558 ◽

2021 ◽

Vol 7 (2) ◽

pp. e558

Author(s):

Daphne J. Smits ◽

Rachel Schot ◽

Martina Wilke ◽

Marjon van Slegtenhorst ◽

Marie Claire Y. de Wit ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Variants ◽

Brain Mri ◽

Cerebellar Vermis ◽

Compound Heterozygous ◽

Loss Of Function ◽

Functional Studies ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

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A Japanese girl with mild xeroderma pigmentosum group D neurological disease diagnosed using whole-exome sequencing

Human Genome Variation ◽

10.1038/s41439-020-0109-z ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Takayuki Yokoi ◽

Yumi Enomoto ◽

Tomoko Uehara ◽

Kenjiro Kosaki ◽

Kenji Kurosawa

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Neurological Disease ◽

Xeroderma Pigmentosum ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Skin Symptoms ◽

Group D ◽

Xeroderma Pigmentosum Group D

AbstractWe report a Japanese girl with mild xeroderma pigmentosum group D neurological disease. She had short stature, cataracts, intellectual disability, and mild skin symptoms. However, she was not clinically diagnosed. Using whole-exome sequencing, we identified compound heterozygous pathogenic variants in ERCC2. In the future, the patient may develop skin cancer and her neurological symptoms may progress. Early genetic testing is necessary to clarify the cause of symptoms in undiagnosed patients.

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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 Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

BioMed Research International ◽

10.1155/2019/3530198 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Mei Zhao ◽

Lingling Hou ◽

Huajing Teng ◽

Jinchen Li ◽

Jiesi Wang ◽

...

Keyword(s):

Enzymatic Activity ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Compound Heterozygous ◽

Significant Activity ◽

Argininosuccinate Lyase ◽

Chinese Han ◽

Lyase Deficiency ◽

Pathogenic Variants ◽

Whole Exome

Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

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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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Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination – A Case Report

Biomedicine Hub ◽

10.1159/000511389 ◽

2020 ◽

Vol 5 (3) ◽

pp. 1-6

Author(s):

Priya Prasher ◽

Katherine Redmond ◽

Hillarey Stone ◽

James Bailes ◽

Edward Nehus ◽

...

Keyword(s):

Case Report ◽

Promoter Region ◽

Molecular Genetic ◽

Missense Variant ◽

Compound Heterozygous ◽

Molecular Genetic Testing ◽

Coding Region ◽

Polycystic Kidney ◽

Homozygous State ◽

Pathogenic Variants

We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the PMM2gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

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

Reproductive Sciences ◽

10.1007/s43032-021-00835-5 ◽

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.

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Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease

Bioscience Reports ◽

10.1042/bsr20180872 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 2

Author(s):

Qin Xiang ◽

Yanna Cao ◽

Hongbo Xu ◽

Yi Guo ◽

Zhijian Yang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Retinal Pigment ◽

Han Chinese ◽

Chinese Family ◽

Compound Heterozygous ◽

Stargardt Disease ◽

Pathogenic Variants ◽

Whole Exome

Abstract Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.

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Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias

Sexual Development ◽

10.1159/000518091 ◽

2021 ◽

pp. 1-7

Author(s):

Barbara Leitao Braga ◽

Nathalia Lisboa Gomes ◽

Mirian Y. Nishi ◽

Bruna L. Freire ◽

Rafael L. Batista ◽

...

Keyword(s):

Gestational Age ◽

Small For Gestational Age ◽

Massively Parallel Sequencing ◽

Genetic Defect ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Mulibrey Nanism ◽

New Genes ◽

Whole Exome ◽

Undetermined Etiology

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.

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