Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A De Novo case of autosomal dominant mitochondrial membrane protein-associated neurodegeneration.

ABSTRACT:

Background

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a genetic neurodegenerative condition previously thought to be inherited only in an autosomal recessive pattern through biallelic pathogenic variants in C19orf12. Recent evidence has proposed that MPAN can also follow autosomal dominant forms of inheritance. We present a case of a de novo pathogenic variant in C19orf12 identified in a female with clinical features consistent with a diagnosis of MPAN, adding further evidence that the disease can be inherited in an autosomal dominant fashion.

Methods

A 17-year-old Hispanic female was born to non-consanguineous healthy parents. She developed progressive muscle weakness and dystonia beginning when she was 12 years old. Trio, whole-exome sequencing with mitochondrial genome sequencing, and deletion/duplication analysis of both nuclear and mitochondrial genomes was performed in December 2019.

Results

Whole-exome sequencing analysis revealed a single de novo variant in C19orf12. The specific variant is c.256C>T (p.Q86X) located in exon 3.

Conclusion

Our clinical report provides further clinical evidence that MPAN can be inherited in an autosomal dominant or recessive fashion. The patient's age of onset and clinical symptoms are very similar to the previous patient published with this specific variant as well as others with heterozygous pathogenic variants in C19orf12 in Gregory et al. 2019. Our case report highlights the importance of considering both autosomal dominant and autosomal recessive version of MPAN with all patients demonstrating clinical features suggestive of MPAN.

SUBMITTER: Fraser S

PROVIDER: S-EPMC8372066 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).

Project description:BackgroundMitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases.MethodsTwo large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation-dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post-mortem brain from affected subjects was examined.ResultsIn two multi-generation non-consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes.ConclusionsWe present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non-mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling.

| S-EPMC6625130 | biostudies-literature

De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

Project description:Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(?)) and c.35_38delTCAA (p.Ile12Lysfs(?)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

| S-EPMC4678788 | biostudies-literature

A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.

Project description:BACKGROUND:Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. METHODS:A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. RESULTS:Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. CONCLUSION:We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.

| S-EPMC5740555 | biostudies-literature

Rehabilitation for Mitochondrial Membrane Protein-Related Neurodegeneration: A Case Study.

Project description:This case report reports the effects of an 18-week physiotherapy program in children with mitochondrial membrane protein-associated neurodegeneration (MPAN). The study involved two brothers, aged 11 and 12, who had been diagnosed with MPAN. The physiotherapy program was divided into three phases and consisted of 18 weeks of training with a pediatric physiotherapist, including balance, coordination, and strengthening exercises. Muscle strength was assessed using pediatric manual muscle testing, functional balance using the Pediatric Berg Balance Test (PBBT), static balance using the Single-Leg Stance Test, dynamic balance using the Functional Reach Test, postural control using the 5-Time Sit-to-Stand Test, and independence using the Functional Independence Measure for Children (WeeFIM). Positive changes were observed in muscle strength, balance, and independence. After Phase I, PBBT scores (younger sibling +4, 8.1%; older +3, 6.8%) were higher than the minimal clinically important difference (MCID=3.66-5.83). After Phase III, although the PBBT scores improved (younger +2, 4.05%; older +1, 2.3%), the older sibling's score was not higher than the MCID. Thus, the two children showed visible improvements in both body structure and function, as well as activity and participation levels.

| S-EPMC10787901 | biostudies-literature

Case report: A novel <i>de novo</i> deletion mutation of <i>DYRK1A</i> is associated with intellectual developmental disorder, autosomal dominant 7.

Project description:BackgroundIntellectual developmental disorder 7 (also named DYRK1A syndrome) is an autosomal dominant disease. The main clinical features of DYRK1A syndrome include intellectual disability, microcephaly, and developmental delay. This study aimed to identify pathogenic variants in a Chinese girl with developmental delay, impaired social interaction, and autistic behavior.Case presentationThe case was a 6-year-old girl. Clinical symptoms of the patient mainly included developmental delay, seizures, autistic behavior and impaired social interaction. The patient presented with microcephaly, bushy eyebrows, a short lingual frenum, binocular esotropia, bilateral valgus and external rotation, and walked with an abnormal gait. Using whole-exome sequencing, we identified a 9,424 bp de novo heterozygous deletion (containing coding exons 10, 11, and 12, and partial sequences of non-coding exon 12) in DYRK1A, which is responsible for DYRK1A syndrome. The DYRK1A variant is classified as pathogenic according to the criteria of the American College of Medical Genetics and Genomics.ConclusionsThe findings of this study augment the data regarding the pathogenic variants of DYRK1A and provide important information for molecular diagnosis.

| S-EPMC10235440 | biostudies-literature

A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia.

Project description:We described a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits. The findings of our patient were compared to an autosomal dominant omodysplasia (OMOD2) family with FZD2 mutation reported in the literature. OMOD2 is a rare skeletal dysplasia and characterized by facial dysmorphism and shortness of the upper extremities and first metacarpal bones. This is the second report which supports the findings of the first family described and points out that heterozygous FZD2 mutations may be disease-causing for OMOD2.

| S-EPMC5701278 | biostudies-literature

Whole-exome sequencing identifies a de novo PDE3A variant causing autosomal dominant hypertension with brachydactyly type E syndrome: a case report.

Project description:BACKGROUND:Autosomal dominant hypertension with brachydactyly type E syndrome caused by pathogenic variants in the PDE3A gene was first reported in 2015. To date, there are only a few reports of this kind of syndrome. Other patients still lack a genetic diagnosis. CASE PRESENTATION:Whole-exome sequencing was performed in an 18-year-old female proband with a clinical diagnosis of hypertension with brachydactyly syndrome. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs). After bioinformatics analysis and healthy control database filtering, we revealed a heterozygous missense PDE3A variant (c.1346G?>?A, p.Gly449Asp). The variant was absent in the ExAC database and located in a highly evolutionarily conserved cluster of reported PDE3A pathogenic variants. Importantly, this variant was predicted to affect protein function by both SIFT (score?=?0) and PolyPhen-2 (score?=?1). After Sanger sequencing, the variant was determined to be absent in the healthy parents of the proband as well as 800 ethnically and geographically matched healthy controls. CONCLUSION:We present a report linking a de novo PDE3A variant to autosomal dominant hypertension with brachydactyly type E syndrome.

| S-EPMC7336660 | biostudies-literature

De novo variants in WDR45 underlie beta-propeller protein-associated neurodegeneration in five independent families.

Project description:BackgroundBeta-propeller protein-associated neurodegeneration (BPAN) is a rare, X-linked dominant neurodegenerative disease mainly characterized by developmental delay, intellectual disability, epilepsy in childhood and dystonia, parkinsonism, dementia in adulthood. BPAN is caused by variants in WD repeat domain 45(WDR45), which is characterized by iron accumulation in the basal ganglia, however, it may be atypical in early brain MRI.MethodsWhole exome sequencing was performed for five parents-offspring trios and phenotype-driven data analyses were conducted. All candidate variants were confirmed by Sanger sequencing.ResultsHere, we report five independent children presented variable degree of developmental delay, intellectual disability, and/or epilepsy. Five de novo variants of WDR45 including four novel truncating variants (one splicing variant, two nonsense variants, and one frameshift variant) were identified. Although their early brain MRI showed no obvious iron accumulation, multifocal spikes, or polyspikes in electroencephalograms (EEG) were observed in four patients.ConclusionOur study reports four patients with new variants in WDR45, which expands the mutation spectrum of WDR45. In addition, our findings provide an early and precise diagnosis basis of BPAN, which is helpful for accurate genetic counseling and prenatal diagnosis.

| S-EPMC7667327 | biostudies-literature

Presence of de novo mutations in autosomal dominant polycystic kidney disease patients without family history.

Project description:At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents.Case series.24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient.Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring.Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found.A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented.Size of patient group. No direct examination of RNA.Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.

| S-EPMC2598385 | biostudies-literature

De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.

Project description:Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa.Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing.A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.

| S-EPMC4786330 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data