EPG5 Variants with Modest Functional Impact Result in an Ameliorated and Primarily Neurological Phenotype in a 3.5-Year-Old Patient with Vici Syndrome

AbstractCongenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (EPG5)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943–9_5943–5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.

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A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

10.1101/409441 ◽

2018 ◽

Cited By ~ 3

Author(s):

David C. Gershlick ◽

Morié Ishida ◽

Julie R. Jones ◽

Allison Bellomo ◽

Juan S. Bonifacino ◽

...

Keyword(s):

Protein Complexes ◽

Genetic Locus ◽

Neurodevelopmental Disorder ◽

Failure To Thrive ◽

The Other ◽

Single Amino Acid ◽

Global Developmental Delay ◽

Compound Heterozygous ◽

Acid Hydrolases ◽

Gene Encoding

AbstractGARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a six-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino-acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully-assembled GARP and EARP complexes. Likely because of this deficiency, the patient’s fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient’s fibroblasts exhibit swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.

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Unusual phenotypes in patients with a pathogenic germline variant in DICER1

Familial Cancer ◽

10.1007/s10689-021-00271-z ◽

2021 ◽

Author(s):

Kateryna Venger ◽

Miriam Elbracht ◽

Julia Carlens ◽

Peter Deutz ◽

Felix Zeppernick ◽

...

Keyword(s):

Wilms Tumor ◽

Pleuropulmonary Blastoma ◽

Global Developmental Delay ◽

Facial Dysmorphism ◽

Compound Heterozygous ◽

Incomplete Penetrance ◽

Developmental Abnormalities ◽

Lung Cysts ◽

Developmental Features ◽

Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

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Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy

BMJ Case Reports ◽

10.1136/bcr-2021-244641 ◽

2021 ◽

Vol 14 (10) ◽

pp. e244641

Author(s):

Petya Bogdanova-Mihaylova ◽

Patricia McNamara ◽

Sarah Burton-Jones ◽

Sinéad M Murphy

Keyword(s):

Corpus Callosum ◽

Autosomal Recessive ◽

Sensory Neuropathy ◽

Rare Condition ◽

Compound Heterozygous ◽

Sensorimotor Neuropathy ◽

Autosomal Recessive Condition ◽

Solute Carrier ◽

Compound Heterozygous Mutations ◽

Clinical Phenotyping

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+–Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.

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DGAT1 mutations leading to delayed chronic diarrhoea: a case report

BMC Medical Genetics ◽

10.1186/s12881-020-01164-1 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Luojia Xu ◽

Weizhong Gu ◽

Youyou Luo ◽

Jingan Lou ◽

Jie Chen

Keyword(s):

Early Onset ◽

Failure To Thrive ◽

Nutritional Therapy ◽

Congenital Disorder ◽

Nutrition Status ◽

Chronic Diarrhoea ◽

Compound Heterozygous ◽

Case Presentation ◽

Delayed Onset ◽

Restriction Diet

Abstract Background Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. Case presentation Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. Conclusions This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

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A Case With 4 de Novo Copy Number Variations With Clinical Features That Overlap 1q43q44 Microdeletion and 3q29 Microduplication Syndromes

Child Neurology Open ◽

10.1177/2329048x18798200 ◽

2018 ◽

Vol 5 ◽

pp. 2329048X1879820

Author(s):

Miriam Kessi ◽

Jing Peng ◽

Lifen Yang ◽

Haolin Duan ◽

Yulin Tang ◽

...

Keyword(s):

Intellectual Disability ◽

Corpus Callosum ◽

Copy Number ◽

De Novo ◽

Copy Number Variations ◽

Language Delay ◽

Global Developmental Delay ◽

Recurrent Infections ◽

Dental Anomalies ◽

Microdeletion Syndrome

1q43q44 microdeletion syndrome is characterized by intellectual disability/global developmental delay, epilepsy, dysmorphic facies, stereotypic movement, language delay, recurrent infections, dental anomalies, and hand and foot anomalies. Microcephaly and corpus callosum dysplasia are present in some cases depending on gene content. 3q29 microduplication syndrome is characterized by intellectual disability, language delay, microcephaly, and dental anomalies. We report the first case with 4 de novo copy number variations with clinical features which overlap 1q43q44 microdeletion and 3q29 microduplication syndromes. Our case presented with global developmental delay, epilepsy, recurrent infections, stereotypic movements, speech delay, microcephaly, facial dysmorphism, bilateral clinodactyly, and small puffy feet with metatarsus varus; however, she had no corpus callosum dysplasia. Our case highlights the role of multiple copy number variations in the occurrence of a certain phenotype. Moreover, it supports the theory that the loss of HNRNPU gene function cannot explain the occurrence of microcephaly and abnormalities of the corpus callosum in 1q43q44 microdeletion syndrome.

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P.133 Expanding the phenotype of TRNT1 mutations to include Leigh syndrome

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.235 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S51-S51

Author(s):

C Gorodetsky ◽

CF Morel ◽

I Tein

Keyword(s):

Developmental Delay ◽

Early Adulthood ◽

Leigh Syndrome ◽

Global Developmental Delay ◽

High Dose ◽

Sideroblastic Anemia ◽

Whole Exome ◽

Mitochondrial Transfer ◽

Neurological Phenotype ◽

Biallelic Mutations

Background: Children with biallelic mutations in TRNT1 have multi-organ involvement with congenital sideroblastic anemia, -B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) as well as seizures, ataxia and sensorineural hearing loss. The TRNT1 gene encodes the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs accounting for phenotypic pleitropy. Neurodegenerative Leigh syndrome has not been previously reported. Methods:Case summary: A Portuguese boy presented with global developmental delay, 2 episodes of infantile Leigh encephalopathy at 8 mo and 4 yr responsive to high-dose steroids, slow neurodegeneration of cognitive, language and motor functions with optic atrophy, pigmentary retinopathy, spasticity, dystonia, and focal dyscognitive seizures, pancytopenia, transfusion dependent sideroblastic anemia, recurrent febrile infections (pulmonary, gastrointestinal), hypernatremia, with tracheostomy dependence at age 5 yr, malabsorption and TPN dependence at 9 yr, and survival to early adulthood. Neuroimaging showed symmetric hemorrhagic lesions in the thalamus, brain stem (periaqueductal grey) and cerebellum consistent with Leigh syndrome but no lactate peak on MRS. Results: Whole exome sequencing identified a homozygous missense pathogenic variant in TRNT1, c.668T>C (p.I223T) in the affected individual. Conclusions: This report expands the neurological phenotype of TRNT1 mutations and highlights the importance of considering this gene in the evaluation of Leigh syndrome.

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Compound heterozygous variants in theLARP7gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37396 ◽

2015 ◽

Vol 170 (1) ◽

pp. 217-219 ◽

Cited By ~ 14

Author(s):

Tina T. Ling ◽

Susanna Sorrentino

Keyword(s):

Short Stature ◽

Developmental Disability ◽

Failure To Thrive ◽

Compound Heterozygous ◽

Compound Heterozygous Variants ◽

Caucasian Female

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169. THE MECHANISM OF SPERMATID MATURATION - A LINK TO TUMOUR SUPPRESSION

Reproduction Fertility and Development ◽

10.1071/srb10abs169 ◽

2010 ◽

Vol 22 (9) ◽

pp. 87

Author(s):

D. Jamsai ◽

S. J. Smith ◽

A. E. O'Connor ◽

D. J. Merriner ◽

C. Borg ◽

...

Keyword(s):

Rna Splicing ◽

Male Fertility ◽

Rna Binding ◽

Ex Vivo ◽

Round Spermatid ◽

Null Alleles ◽

Compound Heterozygous ◽

Binding Motif ◽

Rna Recognition Motif

To comprehensively uncover novel male fertility regulators, we utilised an unbiased forward genetic screen, ENU mutagenesis. Using this approach, we have identified several novel infertile mouse lines including a male-specific infertile line that we designated ‘Joey’. The mutant Joey mice produced no sperm due to an arrest of male germ cells at the round spermatid stage. The mutation was identified in the RNA binding motif 5 (Rbm5) gene that resulted in an arginine to proline substitution within a highly conserved RNA recognition motif of the protein. The substitution of proline is likely to interfere with RNA binding and/or recognition. In humans, the RBM5 gene maps to a region that is frequently deleted in lung cancers. Ex vivo studies have suggested that RBM5 is a tumour suppressor, apoptosis modulator and RNA splicing regulator. To date, the role of Rbm5 has never been liked to male fertility and the Joey line is the only mouse model of Rbm5 dysfunction. Using our RBM5-specific antibody, we showed that RBM5 is expressed in pachytene spermatocytes and round spermatids. Based on the protein localisation, the proposed role of RBM5 in mRNA processing, the onset of the Joey phenotype, and the site of the identified mutation, we hypothesise that the Rbm5 mutant allele results in a hypomorphic protein, and that RBM5 has an essential role in regulating male germ cell mRNA storage, transport and/or translational regulation of mRNAs that are critical for spermatid maturation. Further, we generated mice compound heterozygous of the Joey Rbm5 mutation and Rbm5 null alleles. We showed that the compound heterozygous males are infertile due to spermatid maturation arrest resembling the Joey mutant males. This result further confirmed the identification of the Rbm5 mutation as a cause of infertility in the Joey mice and a crucial role of Rbm5 in male fertility.

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A Case of UDP-Galactose 4′-Epimerase Deficiency Associated with Dyshematopoiesis and Atrioventricular Valve Malformations: An Exceptional Clinical Phenotype Explained by Altered N-Glycosylation with Relative Preservation of the Leloir Pathway

Molecular Syndromology ◽

10.1159/000511343 ◽

2020 ◽

Vol 11 (5-6) ◽

pp. 320-330

Author(s):

Christopher A. Febres-Aldana ◽

Liset Pelaez ◽

Meredith S. Wright ◽

Ossama M. Maher ◽

Anthony J. Febres-Aldana ◽

...

Keyword(s):

Failure To Thrive ◽

Protein Glycosylation ◽

Compound Heterozygous ◽

Atrioventricular Valve ◽

Long Term Outcomes ◽

Computational Tools ◽

Classic Galactosemia ◽

Leloir Pathway ◽

History Of

The generalized form of UDP-galactose-4′-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP-N-acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring N-glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in N-linked protein glycosylation can explain the patient’s phenotype.

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