Application of Whole Exome-Trio Analysis Reveals Rare Variants Associated with Congenital Pouch Colon

Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC’s rare variants from whole exome sequencing (WES) across 18 affected samples in a total of 64 subjects. A Smith–Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using polymerase chain reaction (PCR), we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.

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Author Correction: Whole exome sequencing reveals rare variants linked to congenital pouch colon

Scientific Reports ◽

10.1038/s41598-018-32119-5 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Praveen Mathur ◽

Krishna Mohan Medicherla ◽

Spandan Chaudhary ◽

Mruduka Patel ◽

Prashanth Bagali ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Whole Exome ◽

Congenital Pouch Colon ◽

Pouch Colon

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lnc-EPB41-Protein Interactions Associated with Congenital Pouch Colon

10.20944/preprints201808.0534.v1 ◽

2018 ◽

Author(s):

Sonal Gupta ◽

Nidhi Gupta ◽

Pradeep Tiwari ◽

Saji Menon ◽

Praveen Mathur ◽

...

Keyword(s):

Protein Interactions ◽

Rare Variants ◽

Western India ◽

Clinical Genetic ◽

Whole Exome ◽

Congenital Pouch Colon ◽

Pouch Colon ◽

Non Coding Rnas ◽

North Western

Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to North Western India specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC's rare variants from whole exome sequencing across 18 affected samples in a total of 64 subjects. A Smith-Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using PCR, we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.

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Whole exome-trio analysis reveals rare variants associated with Congenital Pouch Colon

10.1101/2019.12.10.19013680 ◽

2019 ◽

Author(s):

Sonal Gupta ◽

Praveen Mathur ◽

Ashwani Kumar Mishra ◽

Krishna Mohan Medicherla ◽

Prashanth Suravajhala

Keyword(s):

Rare Variants ◽

De Novo ◽

Anorectal Malformations ◽

Open Reading Frames ◽

Missense Mutations ◽

Clinical Genetic ◽

Variants Of Unknown Significance ◽

Whole Exome ◽

Congenital Pouch Colon ◽

Pouch Colon

AbstractAnorectal malformations (ARM) are individually common but Congenital Pouch Colon (CPC), a rare anorectal anomaly causes a dilated pouch in genitourinary tract. We have earlier attempted to understand the clinical genetic makeup of CPC and identified genes responsible for the disease using whole exome sequencing (WES). Here we report our studies of CPC, by identifying de novo heterozygous missense mutations in 16 proband-parent trios and further discover variants of unknown significance which could provide insights into CPC manifestation and its etiology. Our study confirms candidate mutations in genes, viz. C7orf57, C10orf120, C9orf84 and MUC16, CTC1 particularly emphasizing the role of hypothetical genes or open reading frames causing this developmental disorder. Variant validation revealed disease causing mutations associated with CPC and genitourinary diseases which could close the gaps of surgery in bringing intervention in therapies.

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Whole exome sequencing reveals rare variants linked to congenital pouch colon

Scientific Reports ◽

10.1038/s41598-018-24967-y ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 8

Author(s):

Praveen Mathur ◽

Krishna Mohan Medicherla ◽

Spandan Chaudhary ◽

Mruduka Patel ◽

Prashanth Bagali ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Whole Exome ◽

Congenital Pouch Colon ◽

Pouch Colon

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Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽

10.3390/genes12030430 ◽

2021 ◽

Vol 12 (3) ◽

pp. 430

Author(s):

Steven R. Bentley ◽

Ilaria Guella ◽

Holly E. Sherman ◽

Hannah M. Neuendorf ◽

Alex M. Sykes ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Rare Variants ◽

Strong Family History ◽

Disease Mutations ◽

Whole Exome ◽

History Of ◽

Functional Consequences ◽

Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Anna Ka-Yee Kwong ◽

Mandy Ho-Yin Tsang ◽

Jasmine Lee-Fong Fung ◽

Christopher Chun-Yu Mak ◽

Kate Lok-San Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Movement Disorders ◽

Rare Variants ◽

Diagnostic Yield ◽

Neurological Diseases ◽

Genetic Diagnosis ◽

Potential Treatment ◽

Paediatric Patients ◽

Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

International Journal of Molecular Sciences ◽

10.3390/ijms22073625 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3625

Author(s):

Filomena Napolitano ◽

Giorgia Bruno ◽

Chiara Terracciano ◽

Giuseppina Franzese ◽

Nicole Piera Palomba ◽

...

Keyword(s):

Pompe Disease ◽

Rare Variants ◽

Clinical Symptoms ◽

Late Onset ◽

Respiratory Muscles ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Enzyme Replacement ◽

Whole Exome ◽

Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

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