Papers by Pradeep Vasudevan
Nature Genetics
Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TAS... more Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the ‘X-gate’, a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.
American Journal of Medical Genetics Part A
Smith‐Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a varia... more Smith‐Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence‐based management. In addition, in the absence of functional studies, we suggest that the c...
American Journal of Medical Genetics Part A
Sleep apnea is a common disorder that represents a global public health burden.KCNK3encodes TASK-... more Sleep apnea is a common disorder that represents a global public health burden.KCNK3encodes TASK-1, a K+channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a novel developmental disorder with sleep apnea caused by rarede novogain-of-function mutations inKCNK3. The mutations cluster around the ‘X-gate’, a gating motif which controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein coupled receptor pathways, but which can be inhibited by several clinically relevant drugs. These findings demonstrate a clear role for TASK-1 in sleep apnea and identify possible therapeutic strategies.
Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutatio... more Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutations in NPHS2, which encodes the glomerular protein podocin, account for up to 17 % of sporadic and 40 % of familial cases, where they display an autosomal-recessive pattern of inheri-tance. This report describes a non-consanguineous family with three generations of individuals who are either compound heterozygotes for mutations in NPHS2 or who have inherited a mutation and a non-neutral polymorphism (R229Q). As well as providing an aetiological explanation, identi-fying pathogenic mutations and considering genotype-phenotype correlations can provide prog-nostic information and lead to changes in genetic counselling and management.
European Journal of Human Genetics, 2021
Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by... more Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairme...
Journal of Scientific & Industrial Research, 1996
Archives of Disease in Childhood, 2019
IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmen... more IntroductionFetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.MethodsWe reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.ResultsSeven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pat...
BMJ, 2010
This movement disorder has multiple causes
Epilepsy research, Jan 10, 2018
Endocrinology, diabetes & metabolism case reports, 2017
In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually... more In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibli...
American Journal of Medical Genetics Part A, 2016
Steinfeld syndrome (MIM #184705) was first reported in 1982. It is characterised by holoprosencep... more Steinfeld syndrome (MIM #184705) was first reported in 1982. It is characterised by holoprosencephaly and limb defects, however other anomalies may also be present. Following the initial description, three further cases have been reported in the literature. We report on a 23‐year‐old girl, with features of microform holoprosencephaly and bilateral congenital elbow dislocation in association with hypoplastic radial heads. She was identified to have a variant in the CDON gene inherited from her father who had ocular hypotelorism, but no other clinical features. We discuss the clinical features of Steinfeld syndrome, and broaden the phenotypic spectrum of this condition. Structural analysis suggests that this variant could lead to destabilisation of binding of CDON with hedgehog proteins. Further work needs to be done to confirm whether mutations in the CDON gene are the cause of Steinfeld syndrome. © 2016 Wiley Periodicals, Inc.
Prenatal diagnosis, Jan 2, 2015
To report the prenatal ultrasound scan findings in four fetuses from two families postnatally dia... more To report the prenatal ultrasound scan findings in four fetuses from two families postnatally diagnosed with 17q12 microdeletion syndrome on microarray CGH, and review the literature. We report two families presenting with antenatally detected hyperechogenic kidneys. In family 1, the mother had three pregnancies complicated by anhydramnios with bilateral hyperechogenic kidneys; hyperechogenic enlarged cystic kidneys; and bilateral hyperechogenic kidneys with polyhydramnios respectively. In family 2, antenatal ultrasound scans detected hyperechogenic kidneys. A pubmed search for all reported cases of 17q12 deletion between 2005 and 2015 was performed. All publications were reviewed, and findings summarised. Fourteen publications were deemed suitable for literature review; there was a diagnosis of 17q12 deletion with documented antenatal findings in 25 cases. Antenatal renal anomalies were reported in 88% of these cases. Anomalies were documented from 15 weeks, and most common present...
Hormone Research in Paediatrics, 2015
Background: The insulin-like growth factor 1 receptor (IGF IR) gene is located on chromosome 15q2... more Background: The insulin-like growth factor 1 receptor (IGF IR) gene is located on chromosome 15q26.3. Heterozygous 15q26 deletions involving the IGFIR gene are rare, resulting in intrauterine and postnatal growth retardation, developmental delay and microcephaly. Limited evidence exists on the effect of growth hormone (GH) therapy in these cases. Methods: We report a series of cases with 15q26 deletions, including response to GH treatment. Results: Seven children (2 males) presented with short stature [median height standard deviation score (SDS) of -4.8 (range -3.0 to -5.6)]. GH was started at a median age of 5 years (range 1.8 to 12.4) for a median duration of 5.8 years (range 1.0 to 12.4). Median height SDS increased by +0.6 (range 0.1 to 1.0), +1.3 (range 0.1 to 2.4) and +1.4 (range 0.8 to 3.3) after 1 (n = 7), 5 (n = 4) and 10 years (n = 3) of GH treatment, respectively. Four patients reached final height after 5.8 to 12.4 years of GH with a median change in height SDS of +1.1 ...
American Journal of Medical Genetics Part A, 2014
mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arteria... more mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arterial hypertension.
Clinical Kidney Journal, 2014
Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutatio... more Genetic causes of steroid-resistant nephrotic syndrome are being increasingly recognized. Mutations in NPHS2, which encodes the glomerular protein podocin, account for up to 17% of sporadic and 40% of familial cases, where they display an autosomal-recessive pattern of inheritance. This report describes a non-consanguineous family with three generations of individuals who are either compound heterozygotes for mutations in NPHS2 or who have inherited a mutation and a non-neutral polymorphism (R229Q). As well as providing an aetiological explanation, identifying pathogenic mutations and considering genotype-phenotype correlations can provide prognostic information and lead to changes in genetic counselling and management.
Journal of Medical Genetics, 2005
Reading this handbook of "Cardiothoracic" surgery, I am reminded of the Peter Cook & Dudley Moore... more Reading this handbook of "Cardiothoracic" surgery, I am reminded of the Peter Cook & Dudley Moore sketch about the one legged man auditioning for the role of Tarzan: "I love your right leg … I have nothing against your right leg … unfortunately neither do you!" Well, I have nothing against the cardiac surgery side of this book, it is excellent. Unfortunately the Thoracic component is almost non-existent.
Nature Communications, 2021
Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked ... more Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understan...
Molecular Genetics & Genomic Medicine, 2020
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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Papers by Pradeep Vasudevan