Genetic characterisation of children with short stature and GH or IGF1 insensitivity by single gene and whole exome sequencing

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

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Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2

European Journal of Orthodontics ◽

10.1093/ejo/cjaa023 ◽

2020 ◽

Author(s):

Piranit Nik Kantaputra ◽

Prapai Dejkhamron ◽

Worrachet Intachai ◽

Chumpol Ngamphiw ◽

Katsushige Kawasaki ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Upper Limb ◽

Autosomal Recessive ◽

Cleft Lip ◽

Clinical Findings ◽

Protein Model ◽

Whole Exome ◽

Cleft Lip Palate

Summary Background Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. Objective To report for the first time the molecular aetiology of JHS. Patient and methods Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. Results Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. Conclusions Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.

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Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies

Pediatric Rheumatology ◽

10.1186/s12969-019-0349-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Irit Tirosh ◽

Shiri Spielman ◽

Ortal Barel ◽

Reut Ram ◽

Tali Stauber ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Childhood Onset ◽

Whole Exome

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Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-3382 ◽

2016 ◽

Vol 101 (3) ◽

pp. 898-904 ◽

Cited By ~ 25

Author(s):

Felix Schreiner ◽

Michaela Plamper ◽

Gesche Dueker ◽

Stefan Schoenberger ◽

Laura Gámez-Díaz ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cell Sorting ◽

Mononuclear Cells ◽

Fluorescence Activated Cell Sorting ◽

Truncating Mutation ◽

Normal Ranges ◽

Whole Exome ◽

Lrba Deficiency

Abstract Context: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. Objective: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. Case Presentation: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4+/CD25+ and CD25high/FoxP3+ cells were diminished, whereas an unusual CD25−/FoxP3+ population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. Results: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. Conclusion: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.

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Racial and Ethnic Disparities in Genetic Testing for Hearing Loss: a Systematic Review and Synthesis

10.21203/rs.3.rs-484764/v1 ◽

2021 ◽

Author(s):

Stephanie L Rouse ◽

Michelle M Florentine ◽

Emily Taketa ◽

Dylan K Chan

Keyword(s):

Hearing Loss ◽

Native American ◽

Genetic Testing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Ethnic Disparities ◽

Multiple Gene ◽

Whole Exome ◽

Racial Ethnic

Abstract Racial/ethnic disparities in the diagnostic efficacy of genetic testing for hearing loss has been described. These disparities may relate to differences in variant classification between different racial/ethnic groups, which may in turn derive from disparate representation of these groups in the published literature. We sought to quantify racial/ethnic disparities in the published literature on the human genetics of hearing loss. We conducted a search of PubMed for articles describing single-gene, multiple-gene, or whole-exome sequencing for individuals with sensorineural hearing loss. Data on the populations studied, including race/ethnicity and/or region of origin, subjects tested, and method of testing, were extracted. 1,355 unique populations representing 311,092 subjects from 1,165 studies were included. Overall, White and Asian populations and subjects were equivalently represented, but Latinx, Black, and Native American/Hawaiian groups were significantly underrepresented; over 96% of all subjects in the published literature were White or Asian. Within racial/ethnic groups, the majority of subjects derived from a small subset of countries. The observed racial/ethnic disparity was greater for multiple-gene and whole-exome sequencing than for single-gene sequencing. These findings illustrate the large disparity in published literature on the genetics of hearing loss, and demonstrate the need for increased representation of Latinx, Black, and Native American populations.

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Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma

Journal of Experimental Medicine ◽

10.1084/jem.20101597 ◽

2010 ◽

Vol 207 (11) ◽

pp. 2307-2312 ◽

Cited By ~ 215

Author(s):

Minji Byun ◽

Avinash Abhyankar ◽

Virginie Lelarge ◽

Sabine Plancoulaine ◽

Ayse Palanduz ◽

...

Keyword(s):

T Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Human Herpesvirus ◽

Kaposi Sarcoma ◽

Single Family ◽

Inborn Errors ◽

Whole Exome ◽

Classic Kaposi Sarcoma

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.

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

BMC Medical Genomics ◽

10.1186/s12920-021-00920-3 ◽

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.

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Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

10.1101/525683 ◽

2019 ◽

Author(s):

◽

Yen-Chen Anne Feng ◽

Daniel P. Howrigan ◽

Liam E. Abbott ◽

Katherine Tashman ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Focal Epilepsy ◽

Single Gene ◽

European Ancestry ◽

Whole Exome ◽

Genes Encoding ◽

Rare Genetic Variation ◽

Generalized Epilepsy

AbstractSequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

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Whole Exome Sequencing in Idiopathic Short Stature: rare mutations affecting growth

10.21203/rs.2.16842/v1 ◽

2019 ◽

Author(s):

Shahab Noorian ◽

Farzaneh Rohani ◽

Shahram Savad ◽

Kourosh Kabir ◽

Nami Mohammadian Khonsari ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorders ◽

Correct Diagnosis ◽

Test Results ◽

Rare Mutations ◽

Whole Exome ◽

Common Causes ◽

Blood Specimens

Abstract Introduction: one of the most common causes of referrals to paediatricians is short stature (ISS), some pathogenic mutations may present exactly similar to non-pathogenic causes, our goal is to identify and treat these patients labelled ISS with these mutations and hopefully treat them correctly. Materials and Methods: We assessed All children under the age of fifteen years labelled as ISS. Fourteen of them were confirmed to be ISS and thus were allowed in our study. Afterwards, we pooled their blood specimens and ordered a whole-exome sequencing (WES) test. Results: five patient had normal WES results. Four patients had rare motions that were not studied in the previous literature but due to the functions of the genes, and our patients’ phenotypes it is highly possible that these mutations caused our patients’ short stature. Four patients had known genetic mutations causing short stature. One patient had a mutation with no effect on height. With the help of WES, some rare mutations were found, with the patients’ phenotype and evaluation we identified their function, we diagnosed some other patients’ rare genetic disorders and assessed the possible effect of their mutation on their height and phenotype we aimed to determine how many children labelled as ISS are correctly diagnosed. By WES most of our patient achieved the correct diagnosis which would be impossible to diagnose without WES; thus the reason for their short stature was identified, with the correct diagnosis now we can aim for the proper treatment.

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