This study reports on biallelic homozygous and monoallelic
variants in
in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement ...characterized by microcephaly, intellectual disability, seizures, and global developmental delay.
encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (
) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.
Background
Adult‐onset Nieman–Pick disease type C (NPC) is a rare progressive ataxia caused by lysosomal accumulation of unesterified cholesterol resulting in severe disability and death. The ...diagnosis of NPC can be challenging as clinical features overlap with other more common hereditary ataxias. This study pursued the molecular genetic basis of adult‐onset cerebellar ataxia manifesting in two siblings. A prior diagnosis of spinocerebellar ataxia type 2 (SCA2) based on an ataxia gene panel was questioned when the younger sibling developed similar symptoms but had discordant genetic results.
Methods
Neurologic examination, whole exome sequence (WES), targeted sequence to establish genome phasing, and cytochemical and biochemical studies of fibroblast cultures were employed.
Results
The pedigree and neurological examinations suggested a recessive or possibly dominant cerebellar ataxia. WES showed the siblings were both compound heterozygous for two rare variants in the NPC1 gene—one pathogenic, stop gain at p.Arg934Ter (NM_000271.4), and a missense change, p.Pro471Leu (NM_000271.4), of uncertain significance. Filipin staining of fibroblast cultures showed lysosomal cholesterol accumulation and biochemical assay demonstrated impaired cholesterol esterification.
Conclusions
The study established the correct molecular diagnosis of biallelic, adult‐onset NPC in a patient initially diagnosed with SCA. Additionally, the p.Pro471Leu variant was identified as likely pathogenic. Inaccurate molecular diagnosis will deprive NPC patients of treatment options. Investigation using WES is justified when a detected expansion size is in the borderline range for pathogenicity.
We present a sibling pair who were initially diagnosed with adult‐onset spinocerebellar ataxia Type 2 based on borderline repeat expansion in one sibling. Whole exome sequencing revealed two rare variants including the novel variant p.Pro471Leu associated with NPC. Biochemical testing in both siblings confirmed the diagnosis of NPC, a treatable neurovisceral disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The author describes an experience in Morocco that provided her with an unconventional view of genetic counseling in a unique population, one that was distinct from a traditionally North American ...model of genetic counseling. Part of a special journal issue focused on 'defining moments' in genetic counselor professional development. Authors for this issue were asked to reflect on personal experiences or events, personal or professional, that led to the realization about one's self as a genetic counselor. Adapted from the source document.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES ...in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60 %. Consanguinity and positive family history predicted a higher diagnostic yield. In 5 % (7/149) of cases, CES implicated novel candidate disease genes (
MANF
,
GJA9
,
GLG1
,
COL15A1
,
SLC35F5
,
MAGE4
,
NEUROG1
). CES uncovered two coexisting genetic disorders in 4 % (6/149) and actionable incidental findings in 2 % (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
To describe the phenomenology of cervical dystonia (CD) in patients with migraine and the effect of its treatment on migraine frequency.
Background
Preliminary studies demonstrate that ...treatment of CD with botulinum toxin in those with migraine can improve both conditions. However, the phenomenology of CD in the setting of migraine has not been formally described.
Methods
We conducted a single‐center, descriptive, retrospective case series of patients with a verified diagnosis of migraine who were referred to our movement disorder center for evaluation of co‐existing, untreated CD. Patient demographics, characteristics of migraine and CD, and effects of cervical onabotulinumtoxinA (BoTNA) injections were recorded and analyzed.
Results
We identified 58 patients with comorbid CD and migraine. The majority were female (51/58 88%) and migraine preceded CD in 72% (38/53) of patients by a mean (range) of 16.0 (0–36) years. Nearly all the patients had laterocollis (57/58) and 60% (35/58) had concurrent torticollis. Migraine was found to be both ipsilateral and contralateral to the dystonia in a comparable proportion of patients (11/52 21% vs. 15/52 28%). There was no significant relationship between migraine frequency and dystonia severity. Treatment of CD with BoTNA reduced migraine frequency in most patients (15/26 58% at 3 months and 10/16 63% at 12 months).
Conclusions
In our cohort, migraine often preceded dystonia symptoms and laterocollis was the most described dystonia phenotype. The lateralization and severity/frequency of these two disorders were unrelated, but dystonic movements were a common migraine trigger. We corroborated previous reports that cervical BoTNA injections reduced migraine frequency. Providers treating patients with migraine and neck pain who are not fully responding to typical therapies should screen for possible CD as a confounding factor, which when treated can reduce migraine frequency.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains ...poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC
(CTSK
CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2
CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans
, solely in CTSK
CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK
CSCs and a corresponding expansion of DDR2
CSCs, with DDR2
CSC expansion being a direct maladaptive response to CTSK
CSC depletion. DDR2
CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2
CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2
CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK
CSCs. Finally, the human counterparts of DDR2
CSCs and CTSK
CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary ...spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years standard deviation (SD), range 0.2-5.0, the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
Pathogenic de novo variants in the X‐linked gene SLC35A2 encoding the major Golgi‐localized UDP‐galactose transporter required for proper protein and lipid glycosylation cause a rare type of ...congenital disorder of glycosylation known as SLC35A2‐congenital disorders of glycosylation (CDG; formerly CDG‐IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N‐glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2‐CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2‐dependent UDP‐galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild‐type to mutant alleles in fibroblasts from affected individuals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
The effectiveness of next generation sequencing at solving genetic disease has motivated the rapid adoption of this technology into clinical practice around the world. In this study, we use ...whole exome sequencing (WES) to assess 48 patients with Mendelian disease from 30 serial families as part of the “Qatar Mendelian Disease pilot program” – a coordinated multi-center effort to build capacity and clinical expertise in genetic medicine in Qatar. By enrolling whole families (parents plus available siblings), we demonstrate significantly improved discriminatory power for candidate variant identification over trios for both de novo and recessive inheritance patterns. For the same index cases, we further demonstrate that even in the absence of families, variant prioritization is improved up to 8-fold when a modest set of population-matched controls is used vs large public databases, stressing the poor representation of Middle Eastern alleles in presently available databases. Our in-house pipeline identified candidate disease variants in 27 of 30 families (90%), 23 of which (85%) harbor novel pathogenic variants in known disease genes, pointing to significant allelic heterogeneity and founder mutations underlying Mendelian disease in the Middle East. For 6 of these families, the clinical presentation was only partially explained by the candidate gene, suggesting phenotypic expansion of known syndromes. Our pilot study demonstrates the utility of WES for Middle Eastern populations, the dramatic improvement in variant prioritization conferred by enrolling population-matched controls and/or enrolling additional unaffected siblings at the point-of-care, and 25 novel disease-causing alleles, relevant to newborn and premarital screening panels in regional populations.
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