Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, ...but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.
Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with ...wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.
Objective
Pathogenic variants in SCN3A, encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the ...spectrum of clinical, genetic, and neuroimaging features of SCN3A‐related neurodevelopmental disorder.
Methods
Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293T cells).
Results
Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.
Interpretation
Our study defines SCN3A‐related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348–362
Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined ...clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid ...disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected ...parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
Intellectual disability (ID) is a neurodevelopmental condition that affects ~1% of the world population. In total 5-10% of ID cases are due to variants in genes located on the X chromosome. Recently, ...variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (OGT), an essential enzyme that catalyses O-linked glycosylation with β-N-acetylglucosamine (O-GlcNAc) on serine/threonine residues of thousands of nuclear and cytosolic proteins. In this review, we compile the work from the last few years that clearly delineates a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation (OGT-CDG). We discuss potential hypotheses for the underpinning molecular mechanism(s) that provide impetus for future research studies geared towards informed interventions.
The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane ...potential, and are required for action potential production.
-null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in
associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm.
mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation.
The L74P STIM1 change within the EF-hand domain precedes the first Ca2+-binding aspartate residue by 2 amino acids (see Fig E2) and therefore might be expected to distort the Ca2+-binding region of ...the protein. ...we compared the response of mutant YFP-STIM1 (L74P) with the depletion of Ca2+ stores after thapsigargin or cyclopiazonic acid (CPA) treatment with that of wild-type YFP-STIM1 and the previously published EF-hand mutant7 YFP-STIM1 (D76A, see Fig E3 in this article's Online Repository at www.jacionline.org). Feature Recessive homozygous mutations Dominant mutations Reference Picard et al, 2009E8 Byun et al, 2010E9 Fuchs et al, 2012E10 Wang et al 2014E11 Schaballie et al, 2015E12 This study Bohm et al, 2013E13 Morin et al, 2014E14 Individual (AR) or diagnosis (AD) Pr1, Pr2, and Pr3low * Pr4dagger Pr5 and Pr6 Pr7 Pr8 and Pr9 V2 and V3 Tubular aggregate myopathydouble dagger Stormorken syndromedouble dagger Predicted protein effect of mutation No protein No protein p.429 R>C p. 146A>V p.165P>Q p.74 L>P All missense in the EF-hand p.304 R>W Age at last examination (y) 1, 5, 6, and 9 2 1.7 and 6 6 8 and 21 11 and 21 Various Various Immune deficiency Life-threatening infections Life-threatening infections Life-threatening infections History of frequent throat infections: no immunologic evaluation performed Life-threatening infections No persistent severe infection NR NR Other immune dysregulation AIHAITP AIHA AIHAITP NR Colitis, psoriasis V3 transient ITP NR NR Skeletal muscle Developmental skeletal myopathy with hypotonia, profound NR Developmental skeletal myopathy with hypotonia, mild NR Developmental skeletal myopathy, profound No abnormalities Clinical myopathy except with 1 mutation Increased CK typical Clinical myopathyIncreased CK Mydriasis Yes NR Yes NR No No NC Yes Sweat glands NC NR Anhidrosis NR Anhidrosis Hypohidrosis NC NC Dental enamel Abnormal NR Abnormal Abnormal Abnormal Abnormal NC NC Died Pr1 died 9 y (during HSCT)Pr2 died 1.5 y (encephalitis) Pr4 died 2 y (Kaposi sarcoma) Pr6 died 1.7 y (sepsis) NR NA NA NA NA Alive Pr3 alive at 6 y (HSCT at 1.3 y) NA Pr5 alive (HSCT) Pr7 lost to follow-up at 5 y Pr8 and Pr9 alive V2 and V3 alive All alive All alive Table E3 Summary of key clinical findings associated with individual reported recessive STIM1 mutations and summarized key clinical findings associated with dominant STIM1 mutations AIHA, Autoimmune hemolytic anemia; AD, autosomal dominant; AR, autosomal recessive; CK, creatine kinase; HSCT, hematopoietic stem cell transplantation; ITP, idiopathic thrombocytopenic purpura; NA, not applicable; NC, no comment made; NR, comment made but feature not recognized.
Mohr-Tranebjærg syndrome is an X-linked syndrome characterized by sensorineural hearing impairment in childhood, followed by progressive neurodegeneration leading to a broad phenotypic spectrum. ...Genetically MTS is caused by pathogenic variants in the TIMM8A gene, including gene deletions and larger contiguous gene deletions. Some of the latter involve the neighboring gene BTK, resulting in agammaglobulinemia. By next-generation mate-pair sequencing we have mapped the chromosomal deletion breakpoints of one MTS case and three XLA-MTS cases and used breakpoint-spanning PCR to fine map the breakpoints by Sanger sequencing. Two of the XLA-MTS cases presented with large deletions (63.5 and 27.2 kb), and the junctional regions were characterized by long stretches of microhomology, indicating that the events have emerged through homologous recombination. Conversely, the MTS case exhibited a small 2 bp region of microhomology, and the regions were not characterized by extensive microhomology. The third XLA-MTS case had a more complex breakpoint, including a 59 bp inverted insertion, thus at least four breakpoints were involved in this event. In conclusion, mate-pair library generation combined with next-generation sequencing is an efficient method for breakpoint identification, also in regions characterized by repetitive elements.
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