A mild form of adenylosuccinate lyase deficiency in absence of typical brain MRI features diagnosed by whole exome sequencing

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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Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

BioMed Research International ◽

10.1155/2019/3530198 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Mei Zhao ◽

Lingling Hou ◽

Huajing Teng ◽

Jinchen Li ◽

Jiesi Wang ◽

...

Keyword(s):

Enzymatic Activity ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Compound Heterozygous ◽

Significant Activity ◽

Argininosuccinate Lyase ◽

Chinese Han ◽

Lyase Deficiency ◽

Pathogenic Variants ◽

Whole Exome

Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

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SAT-081 Hidden in Plain Sight: Rethinking Our Approach to Allan-Herndon-Dudley Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1543 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Alyssa M Dye ◽

Grace Bazan Nelson ◽

Alicia Marie Diaz-Thomas

Keyword(s):

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

Brain Mri ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Neurological Manifestations ◽

Free T4 ◽

Phase 2 Trial ◽

Whole Exome

Abstract Background: Allan-Herndon-Dudley (AHD) is a rare X-linked disorder with neurological manifestations secondary to a mutation in monocarboxylate transporter 8, a protein that transports T3 into nerve cells in the brain. AHD is characterized by increased serum free T3, decreased serum free T4 and normal serum TSH levels as well as the severe neurological manifestations including global developmental delay, hypotonia, and joint contractures (1). A phase 2 trial using triodyothyroacetic acid has shown promise in treating this disorder (2). We report on three children who were diagnosed by whole exome sequencing after presenting with neurological manifestations. Clinical Cases: Patient 1 presented at 4 months to the neurology clinic for seizures. He had a normal newborn screen. Worsening developmental delays and central hypotonia prompted a brain MRI that revealed delayed myelination for age. At 6 months a chromosomal microarray and metabolic work-up were performed and were nondiagnostic. Whole exome sequencing was obtained at the age of 4.5 years revealing a mutation in the SLC16A2 gene (p.Ser210Tyr). Thyroid studies were consistent with the diagnosis. Patient 2 presented to neurology at 9 months for developmental delay. A brain MRI was obtained which was within normal limits. At 14 months an acylcarnitine profile was obtained which indicated a possible CPT1 deficiency, which did not fit his clinical picture. Chromosomal microarray as well as work-up for inborn errors of metabolism were performed and were nondiagnostic. Thyroid studies were obtained which showed low free T4 with normal TSH. Whole exome sequencing was obtained at the age of 2.5 years, which revealed a mutation in SLC16A2 (p.R371C). Patient 3 presented as sibling of patient 2 with known AHD syndrome. Testing for SLC16A2 was performed at the age of 5 months and returned positive for same mutation as sibling (p.R371C). Conclusion: Allan-Herndon-Dudley syndrome is a rare neurological disease secondary to a mutation in the T3 transporter protein to nervous tissue. A high index of suspicion as well as thyroid studies should be obtained in patients presenting with central hypotonia and global developmental delay with normal newborn screens, particularly in states that use TSH as a screening test. This is especially important as treatments are becoming available that may help prevent neurological devastation seen in these patients. References: 1. Dumitrescu AM, Fu J, Dempsey MA, Refetoff S. MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993 2. Groeneweg S, Peeters RP, Moran C, et al. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(9):695-706.

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Новая гомозиготная мутация в гене ARL6IP1 - второй случай редкой спастической параплегии

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2019.02.42-48 ◽

2020 ◽

pp. 42-48

Author(s):

А.Л. Чухрова ◽

И.А. Акимова ◽

О.А. Щагина ◽

В.А. Кадникова ◽

О.П. Рыжкова ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Sanger Sequencing ◽

Brain Mri ◽

Lower Limbs ◽

Causative Mutation ◽

Spastic Paraplegia ◽

Exon 2 ◽

Whole Exome

Актуальность. Наследственные спастические параплегии (НСП) - обширная, высоко гетерогенная группа нейродегенеративных заболеваний, характеризующихся прогрессирующим нижним спастическим парапарезом, вызванным поражением кортико-спинального тракта. Постоянно растущее число генов (картировано более 80 локусов, известно 60 генов), ассоциированных с НСП, осложняет постановку точного диагноза. Это особенно актуально для форм НСП, где описаны единичные случаи заболевания, как, например, для аутосомно-рецессивной спастической параплегии типа 61 (SPG61, OMIM: 615685). Введение в практику новых технологий секвенирования позволяет сократить время исследования и выявить молекулярно-генетическую причину заболевания в большинстве случаев, особенно в семьях с редкими НСП. Цель - описать клиническую картину редкой осложненной НСП с ранним началом (SPG61) в семье даргинцев, состоящих в близкородственном браке, и установить ее молекулярно-генетическую причину. Материалы и методы: семейный анамнез, неврологическое обследование, электроэнцефалография, МРТ головного мозга, выделение ДНК, секвенирование полного экзома, анализ данных полноэкзомного секвенирования, секвенирование по Сэнгеру. Результаты. В результате секвенирования полного экзома с последующим анализом полученных данных был обнаружен не описанный ранее гомозиготный вариант нуклеотидной последовательности c.[92T>C];[92T>C] (p.[(Leu31Pro)];[(Leu31Pro)], NM_015161.1) в экзоне 2 гена ARL6IP1 - второй вариант, найденный в этом гене в мире и первый в России. Наличие выявленного варианта было подтверждено методом прямого автоматического секвенирования по Сэнгеру. Вариант c.92T>C был зарегистрирован в гомозиготном состоянии у обоих пациентов и в гетерозиготном состоянии у родителей, тем самым была показана его сегрегация с заболеванием в данной семье. В статье приведено подробное описание клинических проявлений заболевания в данной семье и сравнение клинических проявлений у больных в двух семьях с выявленными изменениями в гене ARL6IP1 (описанной ранее и изученной нами). Выводы. Проведенное исследование дополняет характеристику клинических проявлений, связанных с изменениями в гене ARL6IP1, приводящих к осложненным НСП с ранним началом. Background. Hereditary spastic paraplegias (HSPs) are a large group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness caused by a retrograde axonal degeneration of the corticospinal tracts. The considerable and constantly increasing number of HSP-associated genes (more than 80 different loci with 60 corresponding spastic paraplegia genes) complicates the diagnosis in every particular case, especially with a single reported occurrence like the autosomal recessive spastic paraplegia 61 (SPG61, OMIM: 615685). However, new sequencing methods allow to accelerate the process and find the molecular cause of the disease much more reliably, especially in families with rare HSPs. Aims. To describe a rare complicated early-onset HSP (SPG61) in a Dargin consanguineous family and find out its molecular genetical cause. Materials and methods: personal and family history analysis, neurological examination, electroencephalography, brain MRI, blood DNA extraction, whole exome sequencing (WES), WES data analysis, Sanger sequencing. Results. During a session of whole-exome sequencing and analysis, a new homozygous variant c.[92T>C];[92T>C] (p.[(Leu31Pro)];[(Leu31Pro)], NM_015161.1) has been discovered in exon 2 of the ARL6IP1 gene, which makes it the second variant found in this gene worldwide and the first one in Russia. Sanger sequencing of the patients’ and parents’ DNA confirmed the p.(Leu31Pro) variant status (homozygous in both patients and heterozygous in both parents) and its segregation with the disease status. Here we describe the clinical findings of the disease in this family and a clinical data comparison for two families with variants in the ARL6IP1 gene (described previously and studied in our laboratory). Conclusions. Our research broadens the diversity of symptoms associated with ARL6IP1 gene mutations. The discovered variant expands the causative mutation spectrum of complicated early-onset HSPs.

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Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review

Molecular Syndromology ◽

10.1159/000519365 ◽

2021 ◽

pp. 1-6

Author(s):

Daniel Martín Fernández-Mayoralas ◽

Jacobo Albert ◽

Sara López-Martín ◽

Mar Jiménez de la Peña ◽

Ana Laura Fernández-Perrone ◽

...

Keyword(s):

Literature Review ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Male Patient ◽

Neurodevelopmental Disorders ◽

Autosomal Recessive ◽

Brain Mri ◽

Homozygous State ◽

Whole Exome ◽

Synonymous Variant

Bi-allelic mutations in the TUBGCP4 gene have been recently associated with autosomal recessive microcephaly with chorioretinopathy. However, little is known about the genotype-phenotype characteristics of this disorder. Here, we describe a 5-year-old male patient with autism and a normal occipitofrontal circumference. No retinal abnormalities were observed. Brain MRI revealed the presence of enlarged sheaths of both tortuous optic nerves; both eyes had shorter axial lengths. Whole-exome sequencing in trio revealed synonymous TUBGCP4 variants in homozygous state: c.1746G>T; p.Leu582=. This synonymous variant has been previously described and probably leads to skipping of exon 16 of TUBGCP4. These results broaden the clinical spectrum of this new syndrome and suggest that TUBGCP4 bi-allelic mutations may underlie complex neurodevelopmental disorders.

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Genetic Analysis of Undiagnosed Juvenile GM1-Gangliosidosis by Microarray and Exome Sequencing

Case Reports in Genetics ◽

10.1155/2018/8635698 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Ahmed Bouhouche ◽

Houyam Tibar ◽

Yamna Kriouale ◽

Mohammed Jiddane ◽

Imane Smaili ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Brain Mri ◽

Age At Onset ◽

Central Nervous System Involvement ◽

Clinical Spectrum ◽

Chromosomal Microarray ◽

Heterozygous State ◽

Gm1 Gangliosidosis ◽

Whole Exome

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder due to mutations in the lysosomal acid 3-galactosidase gene, GLB1. It is usually classified into three forms, infantile, juvenile, or adult, based on age at onset and severity of central nervous system involvement. Because of their broad clinical spectrum and their similarity to many other aetiologies, including inherited neurodegenerative and metabolic diseases, it is often difficult to diagnose such diseases. Recently, whole exome sequencing (WES) has become increasingly used when a strong hypothesis cannot be formulated based on the clinical phenotype. Here, we present three patients belonging to a consanguineous Moroccan family with a GM1-gangliosidosis with unusual clinical onset and atypical radiological presentation that had eluded diagnosis for over a decade. To identify the disease-causing mutation, we performed a whole exome sequencing and a chromosomal microarray genotyping in order to reduce the number of genetic variants to be interpreted, by focusing the data analysis only on the linked loci. The already known pathogenic missense mutation c.601G>A in GLB1 (p.R201C) was found at homozygous state in the proband V.1 and at heterozygous state in his father IV.1. The mutation was validated by Sanger sequencing and segregated in all the family members according to a recessive mode of inheritance. Outside of the linked loci, we found the EXOSC8 p.Ser272Thr mutation at heterozygous state in all the patients and their mother IV.2. This mutation was reported to cause pontocerebellar hypoplasia type 1C and could act as a modifying factor that exacerbates the brain atrophy of patients. Our study identified the first GLB1 mutation in North Africa in patients with unexpected brain-MRI outcomes extending the clinical spectrum of the GM1-gangliosidosis.

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