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1.
Clin Genet ; 100(5): 628-633, 2021 11.
Article in English | MEDLINE | ID: mdl-34415064

ABSTRACT

Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Intramolecular Transferases/genetics , Mutation , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , Age of Onset , Alleles , Amino Acid Substitution , Computational Biology , Databases, Genetic , Facies , Genetic Association Studies/methods , Homozygote , Humans , Pedigree , Exome Sequencing
2.
Clin Genet ; 100(4): 412-429, 2021 10.
Article in English | MEDLINE | ID: mdl-34216016

ABSTRACT

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.


Subject(s)
Cell Cycle Proteins/genetics , Co-Repressor Proteins/genetics , DNA-Binding Proteins/genetics , Epilepsy/diagnosis , Epilepsy/genetics , Genetic Variation , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , Adolescent , Adult , Alleles , Amino Acid Substitution , Child , Child, Preschool , Databases, Factual , Electroencephalography , Epilepsy/therapy , Epilepsy, Generalized/diagnosis , Epilepsy, Generalized/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Testing , Genotype , Humans , Male , Middle Aged , Mutation , Young Adult
3.
Am J Med Genet A ; 185(12): 3683-3693, 2021 12.
Article in English | MEDLINE | ID: mdl-34296518

ABSTRACT

Longevity of individuals with neurodevelopmental diseases as Rett syndrome (RTT) has increased and many reach adulthood and old age. There is therefore a need to increase knowledge about the course of RTT in adults in order to improve medical care management and quality of life. We did a longitudinal study to address if a possible decline in motor skills in adults with RTT can be explained by the presence of common medical conditions as epilepsy, breathing disturbance, and scoliosis. Data from the Danish RTT database, medical files, and videos from visits at the national Center for Rett syndrome were reviewed. The study included 24 individuals aged 30-66 years at last visit after a follow-up period of 6-12 years. Results showed a clinically observable and significant decline in gross motor skills using the Rett syndrome Gross Motor Scale (RSGMS) with a tendency of less decline in the individuals with the best motor abilities. The frequencies of comorbidities were high. Decline in RSGMS score was associated with the presence of epilepsy and severe scoliosis that had been conservatively managed. The results emphasize that epilepsy plays a significant role in the adult RTT life and management of severe scoliosis in the younger years has impact on the motor abilities in adulthood.


Subject(s)
Longevity/genetics , Motor Skills Disorders/physiopathology , Neurodevelopmental Disorders/physiopathology , Rett Syndrome/physiopathology , Adult , Aged , Denmark , Epilepsy/complications , Epilepsy/physiopathology , Female , Follow-Up Studies , Humans , Longevity/physiology , Longitudinal Studies , Male , Middle Aged , Motor Skills/physiology , Motor Skills Disorders/complications , Motor Skills Disorders/epidemiology , Neurodevelopmental Disorders/complications , Neurodevelopmental Disorders/epidemiology , Rett Syndrome/complications , Rett Syndrome/epidemiology , Severity of Illness Index
4.
Hum Mutat ; 41(10): 1761-1774, 2020 10.
Article in English | MEDLINE | ID: mdl-32652677

ABSTRACT

Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.


Subject(s)
Kinesins , Mutation, Missense , Family , Female , Heterozygote , Humans , Kinesins/genetics , Mutation , Neurodevelopmental Disorders/genetics , Rett Syndrome/genetics
5.
Ann Neurol ; 86(2): 181-192, 2019 08.
Article in English | MEDLINE | ID: mdl-31177578

ABSTRACT

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.


Subject(s)
Autistic Disorder/diagnosis , Autistic Disorder/genetics , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Gain of Function Mutation/genetics , KCNQ3 Potassium Channel/genetics , Amino Acid Sequence , Child , Child, Preschool , Genetic Variation/genetics , Humans , KCNQ3 Potassium Channel/chemistry , Male , Protein Structure, Secondary , Young Adult
6.
Clin Genet ; 95(3): 403-408, 2019 03.
Article in English | MEDLINE | ID: mdl-30417326

ABSTRACT

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.


Subject(s)
Methyl-CpG-Binding Protein 2/genetics , Mosaicism , Mutation , Phenotype , Rett Syndrome/diagnosis , Rett Syndrome/genetics , Alleles , Biopsy , Child , Facies , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Testing , Humans , Male
7.
Mol Genet Metab ; 120(4): 384-391, 2017 04.
Article in English | MEDLINE | ID: mdl-28336152

ABSTRACT

TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1383Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the "silent" c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.


Subject(s)
Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Skin Diseases/pathology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis/complications , Tumor Suppressor Proteins/genetics , Amino Acid Substitution , Cells, Cultured , Down-Regulation , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Male , Mechanistic Target of Rapamycin Complex 1 , Pedigree , RNA Splicing , Sequence Analysis, DNA , Skin Diseases/genetics , Skin Diseases/metabolism , Tuberous Sclerosis/genetics , Tuberous Sclerosis Complex 2 Protein
8.
Hum Mutat ; 37(2): 148-54, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26507355

ABSTRACT

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).


Subject(s)
Abnormalities, Multiple/genetics , Hearing Loss/genetics , Intellectual Disability/genetics , Mandibulofacial Dysostosis/genetics , Microcephaly/genetics , Mutation , Peptide Elongation Factors/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Amino Acid Motifs , Databases, Genetic , Gene Expression , Haploinsufficiency , Hearing Loss/diagnosis , Hearing Loss/pathology , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Mandibulofacial Dysostosis/diagnosis , Mandibulofacial Dysostosis/pathology , Microcephaly/diagnosis , Microcephaly/pathology , Models, Molecular , Molecular Sequence Data , Penetrance , Phenotype , Protein Structure, Secondary , Protein Structure, Tertiary , RNA Splicing , Spliceosomes/genetics
9.
Orphanet J Rare Dis ; 19(1): 213, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38778413

ABSTRACT

BACKGROUND: Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. RESULTS: Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene-disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene-phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. CONCLUSIONS: This work provides a detailed evidence-based view of the gene-disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene-phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).


Subject(s)
Genetic Testing , Vascular Malformations , Humans , Genetic Testing/methods , Vascular Malformations/genetics , Vascular Malformations/diagnosis , Vascular Malformations/pathology , Genetic Association Studies
10.
Am J Med Genet A ; 161A(9): 2358-62, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23894085

ABSTRACT

Microscopically visible rearrangements of chromosome 4p includes the two well known abnormalities: partial trisomy 4p, and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR 1 and WHSCR2, respectively), which cause well-defined phenotypes including minor anomalies, and developmental delay/intellectual disability. In contrast small duplications of 4p are rare but with the advent of microarray techniques a few cases have been reported in recent years. Here we describe a 3 Mb duplication at 4p16.3 segregating with a characteristic phenotype, macrocephaly, speech delay and mild intellectual disability in a three generation family.


Subject(s)
Chromosome Duplication , Chromosomes, Human, Pair 4 , Intellectual Disability/genetics , Language Development Disorders/genetics , Megalencephaly/genetics , Nondisjunction, Genetic , Child , Chromosome Mapping , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/diagnosis , Language Development Disorders/diagnosis , Megalencephaly/diagnosis , Pedigree , Phenotype
11.
Eur J Med Genet ; 66(12): 104872, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37967791

ABSTRACT

Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important. In Denmark, these needs have been addressed through the establishment of collaborative national networks called Genetic Expert Networks or "GENets". These networks have enhanced patient and family care significantly by bringing together groups of experts in national collaborations. This promotes coordinated clinical care, the dissemination of best clinical practices, and facilitates the exchange of new knowledge.


Subject(s)
Gene Regulatory Networks , Viverridae , Humans , Animals , Health Personnel , Denmark , Genetic Counseling
12.
Eur J Med Genet ; 65(10): 104590, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35964931

ABSTRACT

Mosaic PIK3R1 variants have recently been demonstrated in patients with complex vascular malformations and overgrowth in a syndrome resembling PIK3CA-related overgrowth syndrome (PROS). The PIK3CA-inhibitor, alpelisib, seems to be a promising treatment option for PROS patients. We describe a young boy with overgrowth and a pathogenic mosaic variant in PIK3R1; c.1699A > G, p.(Lys567Glu). He was prenatally suspected of a syndrome on the presence of unusual transient fluctuating subcutaneous edemas and lymphedema of his left shoulder. The pathogenic variant, later found to be causative, was below detection threshold in whole-genome sequencing (WGS) analysis of amniotic fluid. Upon delivery a mosaic pathogenic PIK3R1 variant, was identified by whole-exome sequencing (WES) of a skin biopsy. With no proven treatment options available, and based on the theoretical disease mechanism, alpelisib therapy was initiated at nine months of age. In the first year of treatment growth normalized and the affected vascular and lymphatic tissue regressed. No side effects have been observed. This report underlines the importance of early variant detection in children suspected of having severe mosaic overgrowth, and proves that prenatal diagnosis is possible, enabling prompt treatment. Furthermore, it demonstrates the promising effects of alpelisib in this patient group.


Subject(s)
Musculoskeletal Abnormalities , Vascular Malformations , Child , Class I Phosphatidylinositol 3-Kinases/genetics , Class Ia Phosphatidylinositol 3-Kinase , Early Diagnosis , Female , Humans , Male , Mutation , Precision Medicine , Pregnancy , Syndrome , Thiazoles , Transcription Factors , Vascular Malformations/diagnosis
13.
Am J Med Genet A ; 155A(12): 2964-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22052739

ABSTRACT

Microdeletion of the 17q23.2 region has very recently been suggested as a new emerging syndrome based on the finding of 8 cases with common phenotypes including mild-to-moderate developmental delay, heart defects, microcephaly, postnatal growth retardation, and hand, foot, and limb abnormalities. In this report, we describe two new 17q23.2 deletion patients with mild intellectual disability and sensorineural hearing loss. They both had submicroscopic deletions smaller than the common deleted region for the 8 previously described 17q23.2 microdeletion cases. TBX4 was previously suggested as the responsible gene for the heart or limb defects observed in 17q23.2 deletion patients, but the present cases do not have these features despite deletion of this gene. The finding of sensorineural hearing loss in 5 of the 10 cases, including the present cases, with a microdeletion at17q23.2, strongly suggests the presence of a candidate gene for hearing loss within this region. We screened 41 patients with profound sensorineural hearing loss for mutations of TBX2 and detected no mutations.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17 , Hearing Loss, Sensorineural/genetics , Child , Child, Preschool , Comparative Genomic Hybridization , Female , Hearing Loss, Sensorineural/diagnosis , Humans , Infant , Polymorphism, Single Nucleotide , T-Box Domain Proteins/genetics
14.
Front Neurol ; 11: 163, 2020.
Article in English | MEDLINE | ID: mdl-32265818

ABSTRACT

Background: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterized by motor and vocal tics. The underlying etiology remains largely unknown, and GTS is considered as a complex multifactorial disorder associated with effects of several genes in combination with environmental factors. The inner mitochondrial membrane peptidase, subunit 2 (IMMP2L) has been suggested as one of the susceptibility genes for GTS, and IMMP2L-deficient mouse and human cells show increased levels of mitochondrial oxidative stress and altered cell fate programming. Hence, a potential involvement of IMMP2L-induced mitochondrial dysfunction in GTS pathology is yet to be elucidated. To address this, we investigated mitochondrial function in a group of GTS patients with intragenic IMMP2L deletions and compared with GTS without IMMP2L deletions and healthy controls. Methods: Mitochondrial function in fibroblasts from GTS patients and non-GTS parents (with and without IMMP2L deletions) compared to healthy controls were evaluated by measuring mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial mass, and mitochondrial respiration. In addition, we evaluated apoptosis and senescence. Results: None of the mitochondrial parameters assessed in this study were significantly distinctive when comparing GTS patients with and without IMMP2L deletions against healthy controls or parents with or without IMMP2L deletions, and we did not observe altered cell programming. Conclusion: This study suggests that IMMP2L deletions do not lead to a substantial general mitochondrial dysfunction in GTS fibroblasts. Assessing a large cohort of controls and patients of similar age and gender would possibly reveal small differences in mitochondrial function. However, it is possible that IMMP2L variants affect mitochondrial function during specific instances of stress stimuli or in brain regions suggested to be affected in GTS.

15.
Sci Rep ; 10(1): 9909, 2020 06 18.
Article in English | MEDLINE | ID: mdl-32555378

ABSTRACT

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in the skin and other organs, including brain, heart, lung, kidney and bones. TSC is caused by mutations in TSC1 and TSC2. Here, we present the TSC1 and TSC2 variants identified in 168 Danish individuals out of a cohort of 327 individuals suspected of TSC. A total of 137 predicted pathogenic or likely pathogenic variants were identified: 33 different TSC1 variants in 42 patients, and 104 different TSC2 variants in 126 patients. In 40 cases (24%), the identified predicted pathogenic variant had not been described previously. In total, 33 novel variants in TSC2 and 7 novel variants in TSC1 were identified. To assist in the classification of 11 TSC2 variants, we investigated the effects of these variants in an in vitro functional assay. Based on the functional results, as well as population and genetic data, we classified 8 variants as likely to be pathogenic and 3 as likely to be benign.


Subject(s)
Alternative Splicing , Biomarkers, Tumor/genetics , Mutation , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis/genetics , Cohort Studies , DNA Mutational Analysis , Denmark/epidemiology , Humans , Tuberous Sclerosis/epidemiology , Tuberous Sclerosis/pathology
16.
J Neuromuscul Dis ; 6(2): 241-258, 2019.
Article in English | MEDLINE | ID: mdl-31127727

ABSTRACT

BACKGROUND: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. OBJECTIVE: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. METHODS: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. RESULTS: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. CONCLUSION: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.


Subject(s)
Exome Sequencing/methods , Neuromuscular Diseases/diagnosis , Neuromuscular Diseases/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Young Adult
17.
Disabil Rehabil ; 39(9): 911-918, 2017 05.
Article in English | MEDLINE | ID: mdl-27206693

ABSTRACT

Rett syndrome (RTT) is a neurodevelopmental disorder, which mainly affects females and results in multiple disabilities. Many clinical descriptions of the symptoms and functional abilities have been made medically, though mainly in children with RTT. Previous reports have established that even though the syndrome causes severe psychomotor disability, women with RTT can live long into adulthood. PURPOSE: We aim to describe what to expect from aging women with RTT regarding some of the basic functional abilities that are used in daily activities and that could have an impact on quality of life in these women. METHODS: A team of two medical doctors, a physiotherapist and an educational psychological adviser, performed clinical evaluations of 27 women with RTT in Denmark above 30 years of age and confirmed MECP2 mutation. RESULTS: We found that 63% of the women were able to walk outside their homes and only 11% were not able to walk at all. However, 67% could not transfer from sitting to standing position without support. There was profound difficulties communicating, but 85.1% of the women could either consistently point with their hand or eyes to things of their interest. CONCLUSIONS: Women with RTT are very dependent on caregivers who maintain and rehabilitate their functional abilities. They can often walk short distances unassisted, but do have trouble transferring and thus getting up from a chair on their own. They have severe problems communicating and they often perform subtle signs that can be difficult to recognize. Implications for rehabilitation 3/4 of aging RTT women are household ambulators - daily training of motor functions and focus on assisting the initiation of movements are needed lifelong to maintain walking ability and participation in daily activities More than half of aging women with RTT can grab on to things - persons with hand function should be motivated to use this ability in the context of eating Communication is a difficult task especially for the aging RTT women - Communicative signs, their meaning and how to react to them should be written down for every woman in an easy accessible way to all caregivers The majority of aging RTT women can point out things of interest - they should be given the opportunity to participate in choice making.


Subject(s)
Activities of Daily Living , Quality of Life , Rett Syndrome/physiopathology , Adult , Age Factors , Denmark , Female , Humans , Middle Aged
18.
Eur J Paediatr Neurol ; 19(6): 679-87, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26228846

ABSTRACT

BACKGROUND/PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious. METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012. RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements. CONCLUSION: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.


Subject(s)
Early Diagnosis , Rett Syndrome/diagnosis , Adolescent , Autistic Disorder/genetics , Child , Child, Preschool , Denmark , Developmental Disabilities/genetics , Female , Humans , Methyl-CpG-Binding Protein 2/genetics , Mutation , Phenotype , Rett Syndrome/complications , Rett Syndrome/genetics
19.
Ugeskr Laeger ; 177(27)2015 06 29.
Article in Danish | MEDLINE | ID: mdl-26239739

ABSTRACT

The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis is still clinical as defined by the latest clinical criteria as proposed by Neul and colleagues in 2010. This article presents a short clinical and molecular overview of the latest in Rett syndrome with emphasis on the Danish patients, headlines for making the diagnosis, differential diagnoses and molecular diagnostic possibilities.


Subject(s)
Rett Syndrome/diagnosis , Denmark , Diagnosis, Differential , Disease Progression , Female , Humans , Rett Syndrome/genetics , Rett Syndrome/pathology
20.
Mol Genet Metab Rep ; 3: 5-10, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26937387

ABSTRACT

Disorders caused by defects in the mitochondrial translation system are clinically and genetically heterogeneous. The elongation phase of mitochondrial protein synthesis requires, among many other components, three nuclear-encoded elongation factors: EFTu (TUFM; 602389), EFTs (TSFM; 604723), and EFG1 (GFM1; 606639). Mutations have been identified in the genes encoding all three elongation factors, and they result in combined respiratory chain deficiencies and severe phenotypes with an early fatal outcome. So far, only eleven patients have been reported with mutations in GFM1. Here we describe an additional three patients with novel GFM1 mutations. Our results confirm the tissue-specific effect of GFM1 mutations, since we found only slightly decreased respiratory chain enzyme activities in muscle and fibroblasts, but a severe deficiency in the liver. Hence, a thorough biochemical evaluation is important to guide genetic investigation in patients suspected for a mitochondrial disorder.

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