Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy

Abstract Sporadic occurrences of neurodegenerative disorders including neuroaxonal dystrophy (NAD) have been previously reported in sheep. However, so far no causative genetic variant has been found for ovine NAD. The aim of this study was to characterize the phenotype and the genetic aetiology of an early-onset neurodegenerative disorder observed in several lambs of purebred Swaledale sheep, a native English breed. Affected lambs showed progressive ataxia and stiff gait and subsequent histopathological analysis revealed the widespread presence of axonal spheroid indicating neuronal degeneration. Thus, the observed clinical phenotype could be explained by a novel form of NAD. After SNP genotyping and subsequent linkage mapping within a paternal half-sib pedigree with a total of five NAD-affected lambs, we identified two loss-of-function variants by whole-genome sequencing in the ovine PLA2G6 gene situated in a NAD-linked genome region on chromosome 3. All cases were carriers of a compound heterozygous splice site variant in intron 2 and a nonsense variant in exon 8. Herein we present evidence for the occurrence of a familial novel form of recessively inherited NAD in sheep due to allelic heterogeneity at PLA2G6. This study reports two pathogenic variants in PLA2G6 causing a novel form of NAD in Swaledale sheep which enables selection against this fatal disorder.

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De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01277-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Aristides Hadjinicolaou ◽

Kathie J. Ngo ◽

Daniel Y. Conway ◽

John P. Provias ◽

Steven K. Baker ◽

...

Keyword(s):

Network Analysis ◽

De Novo ◽

Neurodegenerative Disorder ◽

Neurological Diseases ◽

Patient Data ◽

Loss Of Function ◽

Sequencing Data ◽

Gene Variation ◽

Transcriptional Signature ◽

Pathogenic Variants

AbstractPathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

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Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Neurology Genetics ◽

10.1212/nxg.0000000000000558 ◽

2021 ◽

Vol 7 (2) ◽

pp. e558

Author(s):

Daphne J. Smits ◽

Rachel Schot ◽

Martina Wilke ◽

Marjon van Slegtenhorst ◽

Marie Claire Y. de Wit ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Variants ◽

Brain Mri ◽

Cerebellar Vermis ◽

Compound Heterozygous ◽

Loss Of Function ◽

Functional Studies ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

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Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1241-z ◽

2019 ◽

Vol 14 (1) ◽

Author(s):

Niu Li ◽

Yufei Xu ◽

Yi Zhang ◽

Guoqiang Li ◽

Tingting Yu ◽

...

Keyword(s):

Postnatal Growth ◽

Compound Heterozygous ◽

Loss Of Function ◽

Atrioventricular Canal ◽

Multiple Systems ◽

Feeding Difficulties ◽

Functional Studies ◽

Pathogenic Variants ◽

Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

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OR22-05 Rare Biallelic Variants in Obesity-Related Genes in the Madrid Pediatric Obesity Cohort

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.638 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Gabriel Á Martos-Moreno ◽

Ida Hatoum Moeller ◽

Álvaro Martín-Rivada ◽

Luis A Pérez-Jurado ◽

Jesús Argente

Keyword(s):

Childhood Obesity ◽

Severe Obesity ◽

Genetic Disorders ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Loss Of Function ◽

Protein Coding ◽

Pathogenic Variants ◽

Genes Encoding ◽

Biallelic Mutations

Abstract BACKGROUND: Obesity is a heterogenous disease resulting from environmental and genetic factors and is characterized by disordered energy balance, regulated in part by the hypothalamic melanocortin-4 receptor (MC4R), including neuronal ciliary assembly and trafficking pathways.1 Rare loss-of-function variants in genes encoding components of this pathway are associated with severe obesity and hyperphagia, with or without additional features.2 However, such rare genetic disorders may be underestimated due to a lack of genetic screening in individuals with severe obesity.3 Our objective was to identify and characterize rare genetic variants in a Spanish population from Madrid with childhood obesity. Methods: This analysis was conducted from a prospectively-collected cohort of children with obesity, generally with a BMI>+3DS. Participants were sequenced for 35 obesity-related genes, including 23 genes related to Bardet-Biedl (BBS) and Alström syndromes, plus an additional 12 genes associated with non-syndromic, monogenic causes of obesity, to identify individuals with rare (<1% frequency in gnomAD) potentially biallelic (homozygous and compound heterozygous) non-synonymous variants in protein-coding regions. Results: Of the 1019 Spanish patients with obesity, 493 (48.4%) were female and the mean age and BMI were 10.41 ± 3.38 years and 4.38 ± 1.76 SDS (79.8% above +3 SDS), respectively. We identified 26 rare potentially biallelic variants in 25 unique individuals, including 2 individuals with homozygous variants in POMC, 3 individuals with two variants in SRC1, one individual with two variants in ADCY3, and one individual with a homozygous mutation in LEP. In addition, we identified 18 individuals with biallelic mutations in one of 23 BBS or ALMS1 genes, including two individuals with known pathogenic variants and clinically confirmed BBS. Conclusions: Rare and potentially biallelic sequence variants were identified in 25 individuals with childhood obesity. These results support the use of genetic testing for individuals with severe obesity who may be candidates for specific clinical interventions or additional targeted therapies.

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Novel LAMA2 variants identified in a patient with white matter abnormalities

Human Genome Variation ◽

10.1038/s41439-020-0103-5 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Keiko Yamamoto-Shimojima ◽

Hiroaki Ono ◽

Taichi Imaizumi ◽

Toshiyuki Yamamoto

Keyword(s):

Creatine Kinase ◽

White Matter ◽

Muscular Dystrophy ◽

Developmental Delay ◽

Congenital Muscular Dystrophy ◽

Genomic Analysis ◽

Compound Heterozygous ◽

Loss Of Function ◽

White Matter Abnormalities ◽

Pathogenic Variants

AbstractComprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.

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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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Novel Compound Heterozygous Variants in TBCD Gene Associated with Infantile Neurodegenerative Encephalopathy

Children ◽

10.3390/children8121140 ◽

2021 ◽

Vol 8 (12) ◽

pp. 1140

Author(s):

Chih-Ling Chen ◽

Chien-Nan Lee ◽

Yin-Hsiu Chien ◽

Wuh-Liang Hwu ◽

Tung-Ming Chang ◽

...

Keyword(s):

Early Onset ◽

Neurodegenerative Disorder ◽

Failure To Thrive ◽

Compound Heterozygous ◽

Gene Encoding ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Relationship Of ◽

Compound Heterozygotes ◽

Insight Into

Mutations in tubulin-specific chaperon D (TBCD), the gene encoding one of the co-chaperons required for the assembly and disassembly of the α/β-tubulin heterodimers, have been reported to cause perturbed microtubule dynamics, resulting in debilitating early-onset progressive neurodegenerative disorder. Here, we identified two novel TBCD variants, c.1340C>T (p.Ala447Val), and c.817+2T>C, presented as compound heterozygotes in two affected siblings born to unaffected carrier parents. Clinical features included early-onset neurodegeneration, failure to thrive, respiratory failure, hypotonia, muscle weakness and atrophy and seizures. We established the genotype–phenotype relationship of these TBCD pathogenic variants and provided insight into the protein structural alteration that may contribute to this chaperone-associated tubulinopathy.

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Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene

Frontiers in Genetics ◽

10.3389/fgene.2021.620752 ◽

2021 ◽

Vol 12 ◽

Author(s):

Magdalena Klaniewska ◽

Maria Jedrzejowska ◽

Malgorzata Rydzanicz ◽

Justyna Paprocka ◽

Mateusz Biela ◽

...

Keyword(s):

Motor Development ◽

Genetic Diagnosis ◽

Hip Dislocation ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Loss Of Function ◽

Pathogenic Variants ◽

Cognitive Delay ◽

Somatosensory Neurons

PIEZO2 protein is a unique ion channel that converts mechanical impulses into cellular signals in somatosensory neurons and is involved in various mechanotransduction pathways. The recessive PIEZO2 loss-of-function pathogenic variants are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT). Here we present three new DAIPT patients. The genetic diagnosis was established by exome sequencing and let us to identify 6 novel loss-of-function PIEZO2 variants: four splicing (c.1080+1G>A, c.4092+1G>T, c.6355+1G>T, and c.7613+1G>A), one nonsense (c.6088C>T) and one frameshift variant (c.6175_6191del) for which mosaic variant was identified in proband's mother. All patients presented typical symptoms at birth, with congenital contractures, bilateral hip dislocation/dysplasia, generalized hypotonia, transient feeding and difficulties. Two were afflicted by transient respiratory insufficiency. In all children motor development was severely delayed. In one patient, severe cognitive delay was also observed. Moreover, among the cases described by us there is the youngest diagnosed child to date.

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Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

Journal of Child Neurology ◽

10.1177/0883073818811223 ◽

2018 ◽

Vol 34 (2) ◽

pp. 74-80 ◽

Cited By ~ 3

Author(s):

Andrea Accogli ◽

Kether Guerrero ◽

Maria Daniela D’Agostino ◽

Luan Tran ◽

Cécile Cieuta-Walti ◽

...

Keyword(s):

Neuronal Development ◽

Neurodegenerative Disorder ◽

Cerebral Atrophy ◽

Trna Synthetase ◽

Homozygous Mutation ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

The Central Nervous System ◽

And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

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Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000316 ◽

2019 ◽

Vol 5 (2) ◽

pp. e565 ◽

Cited By ~ 2

Author(s):

Chong Sun ◽

Jie Song ◽

Yanjun Jiang ◽

Chongbo Zhao ◽

Jiahong Lu ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Trna Synthetase ◽

Insertion Mutation ◽

Compound Heterozygous ◽

Missense Mutations ◽

Loss Of Function ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

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