scholarly journals Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Gilyazetdinov Kamil ◽  
Ju Young Yoon ◽  
Sukdong Yoo ◽  
Chong Kun Cheon
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Large Scale ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Connective Tissue Diseases ◽  
Cleidocranial Dysplasia ◽  
Facial Features ◽  
Targeted Exome Sequencing

Abstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). Methods Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES. Results For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). Conclusions A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

scholarly journals Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

2016 ◽  
Vol 48 (8) ◽  
pp. e251-e251 ◽  
Author(s):  
Hee Gyung Kang ◽  
Hyun Kyung Lee ◽  
Yo Han Ahn ◽  
Je-Gun Joung ◽  
Jaeyong Nam ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Heterogeneity ◽  
Genetic Diagnosis ◽  
Targeted Exome Sequencing

scholarly journals The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Long Jiang ◽  
Wen-Feng Wu ◽  
Li-Yuan Sun ◽  
Pan-Pan Chen ◽  
Wei Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Diagnosis ◽  
Young Patients ◽  
Targeted Exome Sequencing

scholarly journals P.109 Diagnostic Yield of Targeted Exome Sequencing in West Syndrome

2021 ◽  
Vol 48 (s3) ◽  
pp. S50-S50
Author(s):  
M Parfyonov ◽  
I Guella ◽  
DM Evans ◽  
S Adam ◽  
C DeGuzman ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Heterogeneity ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
West Syndrome ◽  
Global Developmental Delay ◽  
Targeted Exome Sequencing ◽  
Ion Proton

Background: West syndrome (WS) is characterized by the onset of epileptic spasms usually within the first year of life. Global developmental delay with/without regression is common. Advances in high-throughput sequencing have supported the genetic heterogeneity of this condition. To better understand the genetic causes of this disorder, we investigated the results of targeted exome sequencing in 29 patients with WS. Methods: Whole exome sequencing (WES) was performed on an Ion ProtonTM and variant reporting was restricted to sequences of 620 known epilepsy genes. Diagnostic yield and treatment impact are described for 29 patients with WS. Results: A definitely/likely diagnosis was made in 10 patients (34%), which included 10 different genes (ALG13, PAFAH1B1, SLC35A2, DYNC1H1, ADSL, DEPDC5, ARX, CDKL5, SCN8A, STXBP1) known to be associated with epilepsy or WS. Most variants were de novo dominant (X-linked/autosomal) except for ARX (X-linked recessive) and ADSL (autosomal recessive). 4 out of 10 (40%) had a genetic diagnosis with potential treatment implications. Conclusions: These results emphasize the genetic heterogeneity of WS. The high diagnostic yield, along with the significant genetic variability, and the potential for treatment impact, supports the early use of this testing in patients with unexplained WS.

A Further Case of Larsen's Syndrome: Clinical and Genotypic Challenges in Diagnosis

2020 ◽  
Author(s):  
Veronica Arora ◽  
Swasti Pal ◽  
Samarth Kulshreshtha ◽  
Ishwar C. Verma
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Protein Modelling ◽  
Variable Expressivity ◽  
Craniofacial Dysmorphism

AbstractLarsen's syndrome is characterized by dislocation of multiple large joints, digital anomalies, craniofacial dysmorphism, and short stature. In this paper, we describe a case of a 5-month-old boy with a triad of cardinal features in association with other signs. The diagnosis was confirmed by exome sequencing, which led to the identification of a novel missense variant NM_001457.4:c.4928C > G (p.Ala1643Gly) in the FLNB gene. We describe the role of protein modelling for the establishment of pathogenicity of this variant. We also outline the challenges in genetic diagnosis due to variable expressivity of the variant and discuss the clinicogenetic profile of previously reported patients with Larsen's syndrome in India.

scholarly journals A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jing Chen ◽  
Zhongmin Xia ◽  
Yulin Zhou ◽  
Xiaomin Ma ◽  
Xudong Wang ◽  
...  
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Slow Wave ◽  
In Silico ◽  
De Novo ◽  
Triangular Face ◽  
Whole Exome ◽  
Kbg Syndrome

Abstract Background KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome. Case presentation A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident. Conclusions The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.

scholarly journals A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110583
Author(s):  
Tong Qiu ◽  
Qian Dai ◽  
Qiu Wang
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Epileptic Seizures ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

scholarly journals B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

2019 ◽  
Vol 46 (s1) ◽  
pp. S11
Author(s):  
L Gauquelin ◽  
T Hartley ◽  
M Tarnopolsky ◽  
DA Dyment ◽  
B Brais ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Cerebellar Atrophy ◽  
Clinical Findings ◽  
Disease Genes ◽  
Pathogenic Variants ◽  
Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

scholarly journals Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract

2020 ◽  
Vol 9 (3) ◽  
pp. 751 ◽  
Author(s):  
Yo Han Ahn ◽  
Chung Lee ◽  
Nayoung K. D. Kim ◽  
Eujin Park ◽  
Hee Gyung Kang ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Congenital Anomalies ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Korean Children ◽  
Targeted Exome Sequencing ◽  
Genetic Causes ◽  
Pathogenic Variants

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5–20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

scholarly journals Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity

2017 ◽  
Vol 177 (6) ◽  
pp. 485-501 ◽  
Author(s):  
Lucy Shapiro ◽  
Sumana Chatterjee ◽  
Dina G Ramadan ◽  
Kate M Davies ◽  
Martin O Savage ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Candidate Gene ◽  
Short Stature ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Genetic Defect ◽  
Significant Proportion ◽  
Genetic Diagnosis ◽  
Whole Exome

Background GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. Objective To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. Methods We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. Results A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver–Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Conclusions Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.

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