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

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 <i>PMM2</i>gene, 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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STUDY OF CLINICAL CASES OF MYOCHE’S MYOPATHY AND DIFFERENTIAL DIAGNOSIS WITH OTHER TYPES OF ADVERSE MYOPATHIES

Odes’kij medičnij žurnal (The Odessa Medical Journal) ◽

10.54229/2226-2008-2021-5-14 ◽

2021 ◽

Author(s):

K. Sarazhyna ◽

Y. Solodovnikova ◽

A. Son

Keyword(s):

Case Report ◽

Genetic Testing ◽

Skeletal Muscles ◽

Molecular Genetic ◽

Clinical Signs ◽

Lower Limbs ◽

Molecular Genetic Testing ◽

Membrane Repair ◽

Rare Type ◽

A Cell

Markesbery-Griggs myopathy, Miyoshi type (MM) is a rare type of myopathy, a form muscular dystrophy with the main involvement of the lower girdle and distal parts of the legs. Due to complexity of genetic testing, the diagnosis is mainly made on the neurological examination of the patient, which adds value to this case report. The childhood or adolescence onset of the disease is characterized initially by the calf muscles` wasting, accompanied by the severe elevation of the serum creatine kinase, as well as a slowly progressive ascending course. The disease refers to dysferlinopathies with various mutations in the DYSF gene. The dysferlin protein is localized in the plasma membrane and in the T-tubule system of skeletal muscles. Physiologically, skeletal muscles are constantly exposed to micromembrane lesions. Depending on the severity, these damages are restored using various complexes. One of the main reparative complexes is the dysferlin-dependent mechanism. Mutations can lead to a defect in the membrane repair, causing the influx of Ca 2+ into the cell, which leads to a cell`s destruction. There are three genetically identifiable types of Miyoshi myopathy: MMD1, MMD2, MMD3. The main clinical signs of the disease are the muscle weakness and atrophy, with predominant involvement of the distal parts of the lower limbs, especially in the gastrocnemius and plantar muscles. The MM causes tip toe walking disturbances and difficulties in climbing the stairs. Progression of the disease and further atrophy leads to the wasting of the lower girdle muscles, mainly gluteal ones. Peculiarity of these myopathies is the absence of cardiomyopathy, due to the immunity of cardiomyocytes to a deficiency of the protein dysferelin. Diagnosis is made on the basis of muscle biopsy and molecular genetic testing. The gold standard is immunoblotting or immunohistochemistry. One of treatment methods is the use of improperly folded dysferlin (treatment with a proteasome inhibitor MG-132) in fibroblasts with restoration of membrane sealing. The aim of this case report is to present an example of a possible clinical diagnosis of MM in a young man, in the absence of opportunities for molecular genetic testing.

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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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Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Genes ◽

10.3390/genes11111329 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1329

Author(s):

Julia Doll ◽

Barbara Vona ◽

Linda Schnapp ◽

Franz Rüschendorf ◽

Imran Khan ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Splice Site ◽

Genetic Heterogeneity ◽

Bioinformatics Analysis ◽

Molecular Genetic ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Syndromic Hearing Loss ◽

Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

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Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia: a case report

F1000Research ◽

10.12688/f1000research.19006.1 ◽

2019 ◽

Vol 8 ◽

pp. 666

Author(s):

Jamie Willows ◽

Maryam Al Badi ◽

Chloe Richardson ◽

Noel Edwards ◽

Sarah Rice ◽

...

Keyword(s):

Case Report ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Missense Variant ◽

Consanguineous Family ◽

Affected Child ◽

Whole Exome ◽

The Family ◽

Domain Interactions ◽

Molecular Genetic Diagnosis

Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised. Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia. We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features. We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring.

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Aberrant Splicing in the PKD2 Gene as a Cause of Polycystic Kidney Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.v10112342 ◽

1999 ◽

Vol 10 (11) ◽

pp. 2342-2351 ◽

Cited By ~ 1

Author(s):

DAVID M. REYNOLDS ◽

TOMOHITO HAYASHI ◽

YIQIANG CAI ◽

BARBERA VELDHUISEN ◽

TERRY J. WATNICK ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Splice Variants ◽

Missense Variant ◽

Single Base Substitution ◽

Base Substitution ◽

Polycystic Kidney ◽

Single Base ◽

Functional Studies ◽

Pathogenic Variants

Abstract. It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing “second hits” in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2.

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

Journal of Pediatric Genetics ◽

10.1055/s-0041-1733852 ◽

2021 ◽

Author(s):

Nasim Rahmani ◽

Saeed Talebi ◽

Nakysa Hooman ◽

Arezou Karamzade

Keyword(s):

Metabolic Profiling ◽

Compound Heterozygous ◽

Homozygous State ◽

Molecular Defects ◽

Causative Variant ◽

Chorioretinal Atrophy ◽

Pathogenic Variants ◽

Whole Exome ◽

Familial Hypomagnesemia ◽

Compound Heterozygous State

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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Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106213 ◽

2019 ◽

Vol 57 (4) ◽

pp. 245-253 ◽

Cited By ~ 3

Author(s):

Kohji Kato ◽

Yasuyoshi Oka ◽

Hideki Muramatsu ◽

Filipp F Vasilev ◽

Takanobu Otomo ◽

...

Keyword(s):

Core Protein ◽

Early Stage ◽

Critical Role ◽

Missense Variant ◽

Compound Heterozygous ◽

Chondrodysplasia Punctata ◽

Loss Of Function ◽

Skeletal Malformation ◽

Endosomal Membrane ◽

Pathogenic Variants

Background3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.MethodsExome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants.ResultsWe identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs*28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l−/− mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5.ConclusionsOur results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.

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Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

Genes ◽

10.3390/genes11111249 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1249

Author(s):

Edmond Wonkam-Tingang ◽

Isabelle Schrauwen ◽

Kevin K. Esoh ◽

Thashi Bharadwaj ◽

Liz M. Nouel-Saied ◽

...

Keyword(s):

Hearing Impairment ◽

Family Members ◽

In Silico Analysis ◽

Missense Variant ◽

Compound Heterozygous ◽

Multiplex Family ◽

Pathogenic Variants ◽

Gene Panels ◽

Syndromic Hearing Impairment ◽

C 63

DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.

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Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3

Cells ◽

10.3390/cells10123481 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3481

Author(s):

Adela Della Marina ◽

Annabelle Arlt ◽

Ulrike Schara-Schmidt ◽

Christel Depienne ◽

Andrea Gangfuß ◽

...

Keyword(s):

Animal Models ◽

Molecular Genetic ◽

Microscopic Investigation ◽

Muscle Pathology ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Microscopic Studies ◽

Lipid Aggregates ◽

The Impact ◽

Detrimental Impact

Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.

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