scholarly journals Identification of rare-disease genes in diverse undiagnosed cases using whole blood transcriptome sequencing and large control cohorts

2018 ◽  
Author(s):  
Laure Frésard ◽  
Craig Smail ◽  
Kevin S. Smith ◽  
Nicole M. Ferraro ◽  
Nicole A. Teran ◽  
...  
Keyword(s):  
Rare Disease ◽  
Developmental Delay ◽  
Whole Blood ◽  
Disease Diagnosis ◽  
Global Developmental Delay ◽  
Disease Genes ◽  
Compound Heterozygous ◽  
Mendelian Disease ◽  
Rna Seq ◽  
Pathogenic Variants

AbstractRNA sequencing (RNA-seq) is a complementary approach for Mendelian disease diagnosis for patients in whom exome-sequencing is not informative. For both rare neuromuscular and mitochondrial disorders, its application has improved diagnostic rates. However, the generalizability of this approach to diverse Mendelian diseases has yet to be evaluated. We sequenced whole blood RNA from 56 cases with undiagnosed rare diseases spanning 11 diverse disease categories to evaluate the general application of RNA-seq to Mendelian disease diagnosis. We developed a robust approach to compare rare disease cases to existing large sets of RNA-seq controls (N=1,594 external and N=31 family-based controls) and demonstrated the substantial impacts of gene and variant filtering strategies on disease gene identification when combined with RNA-seq. Across our cohort, we observed that RNA-seq yields a 8.5% diagnostic rate. These diagnoses included diseases where blood would not intuitively reflect evidence of disease. We identified RARS2 as an under-expression outlier containing compound heterozygous pathogenic variants for an individual exhibiting profound global developmental delay, seizures, microcephaly, hypotonia, and progressive scoliosis. We also identified a new splicing junction in KCTD7 for an individual with global developmental delay, loss of milestones, tremors and seizures. Our study provides a broad evaluation of blood RNA-seq for the diagnosis of rare disease.

scholarly journals Pitt Hopkins-Like Syndrome 1 with Novel CNTNAP2 Mutation in Siblings

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110553
Author(s):  
Rea Mittal ◽  
Ashutosh Kumar ◽  
Roger Ladda ◽  
Gayatra Mainali ◽  
Ermal Aliu
Keyword(s):  
Developmental Delay ◽  
Focal Epilepsy ◽  
Autism Spectrum ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Gait Abnormality ◽  
Pathogenic Variants ◽  
Obstructive Sleep ◽  
Management Guidance ◽  
Intragenic Deletions

Pitt Hopkins-like syndrome 1 (PTHLS1, OMIM # 610042) is an ultra-rare autosomal recessive condition with a prevalence of <1/1,000,000. Intragenic deletions of CNTNAP2 has been implicated in PTHLS1, however to our knowledge a compound heterozygous deletion of exon 4 and a c.1977_1989del13; p.V660Ffsx9 frameshift variant have not been published previously. In this case report, the proband is a seven year old female with PTHLS1, developmental delay, autism spectrum disorder, focal epilepsy, hypotonia, refractory errors, strabismus, and obstructive sleep apnea. Whole exome sequencing analysis revealed biallelic pathogenic variants of the CNTNAP2 gene. Proband has a three year old sister who has who has a similar phenotype including, developmental delay, epilepsy, gait abnormality, refractory errors, strabismus. Family variants were tested and she shared the same CNTNAP2 variants as her sister. The sisters described highlight two novel variants leading to PTHLS1. Genetic workup is essential in identification and management guidance in these populations.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

scholarly journals Mutations in both SAMD9 and SLC19A2 genes caused complex phenotypes characterized by recurrent infection, dysphagia and profound deafness – a case report for dual diagnosis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yi Zhang ◽  
Victor Wei Zhang ◽  
Chunyi Zhang ◽  
Hongke Ding ◽  
...  
Keyword(s):  
De Novo ◽  
Vitamin B1 ◽  
Recurrent Infection ◽  
Multiple Organ ◽  
Growth Delay ◽  
Compound Heterozygous ◽  
Mendelian Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Low Incidence

Abstract Background Phenotypic difference is general in Mendelian disease. Due to the extremely low incidence for a single disease, phenotype spectrum needs to be expanded. Meanwhile, earlier knowledge says patients who suffered from two kinds of different Mendelian disease are very rare. Case presentation We describe a case of neonatal male with genital anomalies, growth delay, skin hyperpigmentation, chronic lung disease with recurrent infection, anemia, and severe deafness. Without any clear etiology after routine workflow, whole exome sequencing was carried on. A pathogenic de novo SAMD9 mutation and compound heterozygous likely-pathogenic variants in SLC19A2 were identified. Some symptoms were improved after the patient was treated with vitamin B1. Unfortunately, the boy died from sepsis and multiple organ failure before 1 year old. Conclusion Combining the phenotype and clinical progress of treatment, we report that it is the first case of a patient with both MIRAGE syndrome and TRMA syndrome.

scholarly journals Case Report: A Novel Compound Heterozygous Mutation of the FRMD4A Gene Identified in a Chinese Family With Global Developmental Delay, Intellectual Disability, and Ataxia

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuhua Pan ◽  
Xiaoling Guo ◽  
Xiaoqiang Zhou ◽  
Yue Liu ◽  
Jingli Lian ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Intellectual Development ◽  
Scaffolding Protein ◽  
Compound Heterozygous Mutation ◽  
Global Developmental Delay ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Sequencing Data

Background: FERM domain-containing protein 4A (FRMD4A) is a scaffolding protein previously proposed to be critical in the regulation of cell polarity in neurons and implicated in human intellectual development.Case Presentation: We report a case of a 3-year-old boy with corpus callosum anomaly, relative macrocephaly, ataxia, and unexplained global developmental delay. Here, compound heterozygous missense mutations in the FRMD4A gene [c.1830G&gt;A, p.(Met610Ile) and c.2973G&gt;C, p.(Gln991His)] were identified in the proband, and subsequent familial segregation showed that each parent had transmitted a mutation.Conclusions: Our results have confirmed the associations of mutations in the FRMD4A gene with intellectual development and indicated that for patients with unexplained global developmental delay, the FRMD4A gene should be included in the analysis of whole exome sequencing data, which can contribute to the identification of more patients affected by this severe phenotypic spectrum.

scholarly journals Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

2020 ◽  
pp. 1-8
Author(s):  
Lindsey Schmidt ◽  
Karen E. Wain ◽  
Catherine Hajek ◽  
Juvianee I. Estrada-Veras ◽  
Maria J. Guillen Sacoto ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Case Series ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Cortical Dysplasia ◽  
Global Developmental Delay ◽  
Tubulin Genes ◽  
Pathogenic Variants ◽  
Brain Malformations ◽  
History Of

Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is <i>TUBB2A</i>-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the <i>TUBB2A</i> gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in <i>TUBB2A</i> (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of <i>TUBB2A</i>-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.

scholarly journals Case report: Compound heterozygous mutations in AP4M1 gene identified in a Chinese infant with Infantile Spasms and Global developmental delay

2021 ◽  
Author(s):  
Lily Zhang ◽  
Xingbing Jin ◽  
Yaqin Wang ◽  
Yan He ◽  
Haoyu Li
Keyword(s):  
Developmental Delay ◽  
Membrane Trafficking ◽  
Protein Complex ◽  
Adaptor Protein ◽  
Infantile Spasms ◽  
Chinese Patient ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
First Case ◽  
Compound Heterozygous Mutations

Abstract Background: Adaptor protein complex-4 (AP-4), a heterotetrameric protein complex, plays an important role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with spastic tetraplegia, developmental delay and intellectual disability (ID).Case presentation: We report on a Chinese patient with infantile spasms, infantile hypotonia and global developmental delay. Exome sequencing showed compound heterozygous mutations in AP4M1(c.19A>G, p.I7V and c.137C>T, p.P46L).Conclusions: This is the first case of biallelic missense variants lay on the region encoding LH domain, which is important for membrane trafficking via protein–protein and intramolecular binding specificities. Our study expands the molecular spectrum associated with AP-4 deficiency syndrome, and reviews the clinical features of reported patients with AP4M1 mutations.

scholarly journals Novel LAMA2 variants identified in a patient with white matter abnormalities

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.

scholarly journals Mapping RNA splicing variations in clinically accessible and nonaccessible tissues to facilitate Mendelian disease diagnosis using RNA-seq

2020 ◽  
Vol 22 (7) ◽  
pp. 1181-1190 ◽  
Author(s):  
Joseph K. Aicher ◽  
Paul Jewell ◽  
Jorge Vaquero-Garcia ◽  
Yoseph Barash ◽  
Elizabeth J. Bhoj
Keyword(s):  
Rna Splicing ◽  
Disease Diagnosis ◽  
Mendelian Disease ◽  
Rna Seq

scholarly journals Clinical implementation of RNA sequencing for Mendelian disease diagnostics

2021 ◽  
Author(s):  
Vicente A. Yepez ◽  
Mirjana Gusic ◽  
Robert Kopajtich ◽  
Christian Mertes ◽  
Nicholas H. Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Genetic Diagnosis ◽  
Allelic Expression ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Rna Seq ◽  
Aberrant Splicing ◽  
Aberrant Expression ◽  
Routine Diagnostics

Lack of functional evidence hampers variant interpretation, leaving a large proportion of cases with a suspected Mendelian disorder without genetic diagnosis after genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies, and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA-sequencing (RNA-seq) in routine diagnostics. To address these issues, we implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease. We detected on average 12,500 genes per sample including around 60% disease genes - a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than one week from sample preparation to result reporting and provided a median of eight disease genes per patient for inspection. A genetic diagnosis was established for 16% of the WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.

scholarly journals Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

2020 ◽  
Author(s):  
Liling Lin ◽  
Ying Zhang ◽  
Hong Pan ◽  
Jingmin Wang ◽  
Yu Qi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Prenatal Diagnosis ◽  
Developmental Delay ◽  
Hot Spot ◽  
Disease Onset ◽  
Genetic Diagnosis ◽  
Global Developmental Delay ◽  
Genetic Characteristics ◽  
Pathogenic Variants

Abstract Background: The estimated worldwide prevalence of global developmental delay (GDD) and intellectual disability (ID) is 1-3%. Rare monogenic GDD/ID is poorly characterized because its low prevalence limits research. In this study, we aimed to describe the diagnostic courses and clinical and genetic characteristics of a cohort with rare monogenic GDD/ID.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectra of rare monogenic GDD/ID patients. We also conducted a follow-up study on prenatal diagnosis in these families. Mutation pathogenicity was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics. Results:Among 108 patients with rare monogenic GDD/ID, it often took 0.5-4 years and 3-5 referrals to obtain a genetic diagnosis after disease onset. Onset typically occurred before 6 years of age, and patients usually presented moderate to severe GDD/ID. The most common coexisting conditions were epilepsy (68%), facial dysmorphism (14%) and microcephaly (13%). In total, 149 different pathogenic variants were found in 81 different genes among the 108 pedigrees, and 71 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal recessive (AR; 46.3%), autosomal dominant (AD; 37%), and X-linked (XL; 16.7%). GLB1, PLA2G6, SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot mutations were rarely found. By the follow-up, 43 families, including 24 ARID, 13 ADID and 6 XLID families, had undergone prenatal diagnosis. The offspring of 6 ARID, 2 ADID and 2 XLID families had the same pathogenic variants as the probands.Conclusion:Rare monogenic GDD/ID is characterized by early onset, relatively severe symptoms, great clinical variability and genetic heterogeneity. Moreover, timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

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