Papers by Pradeep Vasudevan
Annals of Neurology, Jul 9, 2020
Zaman et al.
Brain
KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPT... more KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn −/− mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape and cell numbers prima...
KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants ... more KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn−/− mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical eviden...
Heterozygous loss-of-function ACTB mutations result in a novel developmental syndrome
Human Mutation, 2021
Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, ... more Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletions including, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERFassociated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264-314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
A comprehensive review of orofacial cleft patients at a university hospital genetic department in the UK
Journal of Cleft Lip Palate and Craniofacial Anomalies, 2019
Background: Cleft lip and palate or isolated cleft palate is one of the most common congenital an... more Background: Cleft lip and palate or isolated cleft palate is one of the most common congenital anomalies with a general prevalence of 1 in 700 live births. The aetiology is considered to be a combination of genetic and environmental factors. Clinical genetics service provides information, diagnosis, counselling, management and support to patients and families with genetic disorders. Materials and Methods: Data collection was carried out retrospectively from the Genetics department database. The details regarding referrals, assessment, genetic tests and outcomes were analyzed. Results: There were 33 cases from 2012 to 2016. The majority of cases (61%) were White British. Others included Caribbean, Chinese, Indian, Other Asian, and other mixed categories. 67% of patients had associated other anomalies ranging from being part of a syndrome to separate entities. 36% had family history of clefts and 24% of family members had anomalies other than cleft. Genetic analysis showed abnormality only in 4 of the cases (12%) and 2 had results of unknown significance. Conclusions: Genetic counselling should be built into the plan of cleft care in a structured manner and made available to both patients and parents. There should be a global approach to improve identification and analysis of functional elements controlling gene expression. Integration of genetics and environmental risk using epigenetics is warranted so that aetiology can be better defined and eventual outcome would be more effective clinical care and prevention.
American Journal of Medical Genetics Part A, 2019
Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transc... more Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari‐1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF‐related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan‐) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes‐Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in ...
Endocrine Abstracts, 2016
Renal anomalies and lymphedema distichiasis syndrome. A rare association?
American journal of medical genetics. Part A, 2017
Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, character... more Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore con...
American journal of human genetics, Jan 21, 2016
Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (... more Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourin...
14q22.3 Microdeletion encompassing OTX2 in a five-generation family with microphthalmia, pituitary abnormalities, and intellectual disability
Ophthalmic genetics, Sep 9, 2016
We report a 3-year-old girl who presented with microphthalmia and pituitary hypoplasia, who was f... more We report a 3-year-old girl who presented with microphthalmia and pituitary hypoplasia, who was found to have a 14q22.3 microdeletion encompassing the OTX2 gene on microarray analysis. The proband was part of a family previously reported in this journal; in 1985 Russell-Eggitt and colleagues identified 15 affected individuals with variable features of intellectual disability, and ocular abnormalities including microphthalmia, anophthalmia, and abnormal peripapillary pigmentation. Alterations and whole gene deletions of the OTX2 gene are known to cause microphthalmia and pituitary dysfunction; however this is the largest family reported highlighting the variable presentation of clinical features. This 3-year-old Caucasian female was diagnosed with bilateral micropthalmia shortly after birth. She was later treated with ocular implants. She had hypotonia as a baby and mild delay in reaching her developmental milestones. Magnetic resonance imaging of the brain identified absence of signal in the posterior pituitary. There was a significant family history of ocular abnormalities, including peripapillary pigmentation, microphthalmia and anophthalmia (Figure 1). Those with a more severe ocular phenotype appeared to have a degree of learning difficulties. The proband was the first individual within the family with a documented pituitary abnormality. There were five early neonatal deaths within the family; all children of affected family members; one with anencephaly, two with multiple malformations, one with a septal heart defect and another grossly normal. Following publication in this journal, genetic testing was undertaken by linkage analysis and candidate gene screening. This identified a deletion within the OTX2 gene. We recently performed oligonucleotide microarray to determine the size of the abnormality. This demonstrated a 0.43Mb deletion at 14q22.3 (chr14:57,166,553-57,592,266 (hg19)). The deletion encompasses five genes, OTX2 being the only one with OMIM morbid entry. The OTX2 gene encodes a transcription factor essential for the normal development of the forebrain and the eye. OTX2 has essential functions from early embryogenesis to adulthood in the retina. Heterozygous OTX2 mutations are associated with severe ocular defects (microphthalmia and anophthalmia), and brain malformations. Pituitary abnormalities may also be present. OTX2 mutations have recently been reported in autosomal dominant pattern dystrophy (PD) of the retinal pigment epithelium. Nolen et al. 2006 reported a patient with anophthalmia, pituitary hypoplasia, and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28; q23.2). Translocation breakpoint analysis identified a 9.66 Mb deleted region on the long arm of chromosome 14 which including OTX2 and other genes associated with the phenotype in their patient. Since then, both point mutations and whole gene deletions of OTX2 have been identified. These are thought to account for approximately 2–3% of cases of anophthalmia/microphthalmia. The two cases of whole gene deletions reported in this paper had a severe ocular phenotype; however there may have been a degree of ascertainment bias. In 2014 Brisset et al. reported three cases of 14q22q23 deletion and reviewed seven previously reported patients. All cases had much larger deletions than seen in our family, and presented with a significant ocular phenotype. They concluded that most of the clinical features could be attributable to OTX2 haploinsufficiency, suggesting that a larger chromosomal deletion does not necessarily cause a more severe phenotype. We report a rare case of inherited 14q22.3 deletion in a very large family presenting with variable features of eye abnormalities (microphthalmia, anophthalmia and peripapillary pigmentation), pituitary anomalies, and learning difficulties. The family highlights the variable presentation of clinical features, as seen in many autosomal dominant conditions. The severity of the ocular phenotype does appear to correlate with degree of intellectual disability, possibly related to a degree of disruption to underlying brain development. TheOTX2 deletion was fully penetrant in this family; however a significant proportion had abnormalities detected only on detailed ophthalmological examination. This supports the idea that whole gene deletions do not necessarily cause a more severe phenotype than mutations withinOTX2. The high incidence of early neonatal death cannot be fully explained by this diagnosis, although it is theoretically possible that undiagnosed pituitary insufficiency may have been a factor in the two cases without major congenital anomalies. We have updated the literature with the results of genetic testing for a family that was previously reported in this journal. The significant number of affected individuals within this family has clearly highlighted the variable presentation for whole gene deletions of OTX2.
Prenat Diagn. 2010 Jan;30(1):49-56. doi: 10.1002/pd.2411. Review of perinatal management of arthrogryposis at a large UK teaching hospital serving a multiethnic population. Navti OB, Kinning E, Vasudevan P, Barrow M, Porter H, Howarth E, Konje Khare, m
Prenatal Diagnosis, 2010
A simple blood test, a cascade of repercussions
Bmj Clinical Research, 2007
Is 15q11.2 microdeletion associated with periventricular nodular heterotopia?
Clinical dysmorphology, 2015
The boy was the first child of healthy, nonconsanguineous parents. He was born at 40 weeks, follo... more The boy was the first child of healthy, nonconsanguineous parents. He was born at 40 weeks, following an unplanned pregnancy, which was uneventful until the time of birth. He was delivered by emergency lower segment Caesarean section, due to fetal distress. His birth weight was 3.66 kg. He was admitted to hospital aged 6 months, with Neisseria meningitidis septicaemia with associated thrombocytopenia and coagulopathy, but made a good recovery. He developed tonic clonic seizures aged 2 years and was subsequently diagnosed with epilepsy. He received assessment for a strabismus aged 5 years. He reached his motor and speech and language milestones at the expected time, however, his performance was ‘below average’ at school, his concentration was poor and he required extra help. He was prone to outbursts of anger and displayed head-butting behaviour. The family history was unremarkable. On review in the genetics clinic aged 8 years, his height, weight and head circumference were all between the 25th and 50th centile. He had a left-sided accessory nipple and a widow’s peak (Fig. 1). The remainder of the examination was within normal limits.
Huntington's disease
InnovAiT, 2012
Huntington's disease (HD) is an inherited neurodegenerative disorder with a prevalence of 1 i... more Huntington's disease (HD) is an inherited neurodegenerative disorder with a prevalence of 1 in 10 000. It is an autosomal dominant condition characterized by involuntary movements, changes in behaviour and cognition as well as psychiatric manifestations. There are currently no treatments that will cure or slow its progression. But, direct mutation testing allows a definitive diagnosis to be given and at-risk individuals to undergo predictive testing if they so wish. HD can be multigenerational in its impact upon a family which means GPs are in a unique position to educate, support and coordinate care for these patients. The aim of this article is to give an overview of HD, including its genetics, clinical features, different types of genetic testing and reproductive options as well as to introduce some of the ethical issues that can arise during a consultation. Many of the concepts covered are applicable to other genetic conditions that GPs may come across in their practice.
A novel mutation in NIPBL3 in a case of Cornelia de Lange syndrome confirmed with genetic testing following intrauterine fetal death
Journal of Clinical Pathology, 2013
Cornelia de Lange syndrome (MIM #122470) is a genetic condition that is characterised by typical ... more Cornelia de Lange syndrome (MIM #122470) is a genetic condition that is characterised by typical facial features, growth restriction, developmental delay, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Characteristic facial features include synophrys, arched eyebrows, long eyelashes, small upturned nose, small widely spaced teeth, long and smooth philtrum with down-turned corners of the mouth and microcephaly.1 Cornelia de Lange syndrome exhibits genetic heterogeneity; heterozygous mutations in five genes ( NIPBL, SMC1A, RAD21, SMC3 and HDAC8 ) of the cohesin complex and its regulators have been found in affected patients.2 The majority (60%) are the result of NIPBL gene mutations.3 Although the majority of cases are de novo, it can be inherited in either autosomal dominant ( NIPBL, SMC3, RAD21 ) or X linked recessive manner ( SMC1A, HDAC8 ). We report an intrauterine fetal death at 41 weeks gestation with clinical features of Cornelia de Lange syndrome. A sample of spleen was stored at postmortem and subsequently DNA was extracted and sent for NIPBL gene testing, which identified a previously unreported de novo mutation, confirming the diagnosis. This allowed definitive confirmation of the diagnosis and the opportunity for prenatal testing in a subsequent pregnancy. We highlight the typical clinical features of this rare condition and demonstrate the importance of obtaining a diagnosis for other family members following a fetal death with suspected underlying genetic …
Status epilepsy in CCM with KRIT1 gene change
European Journal of Paediatric Neurology, 2014
We note with interest the recent publication by Balasubramanian et al., presenting two cases of c... more We note with interest the recent publication by Balasubramanian et al., presenting two cases of children presenting with neurological symptoms associated with KRIT1 Cerebral Cavernous Malformations (CCM). This autosomal dominantly inherited condition associated with increasing numbers of capillary cavity lesions in the cerebral parenchyma. Diagnosis is mainly in adulthood with considerable clinical variability with presenting symptoms including seizures, haemorrhage and neurological deficits but often is incidental in asymptomatic mutation carriers. Wewould like to present a further case identified as having a KRIT1mutation in exon 9 following recent molecular testing to further emphasis the variability in presentation and family history. Our proband (White Caucasian) presented at the age of 37years in status-epilepticus having reported no neurological symptoms previously. Subsequently he has developed epilepsy; neuroimaging revealed multiple cavernous lesions. Further details on the family revealed that his father died of a cerebral haemorrhage at the age of 49 years. Molecular testing of KRIT1 identified a nucleotide deletion, c699del G, which is predicted to result in a frameshift with leucine to phenylalanine amino acid substation at codon 233 and premature termination of the KRIT1 protein 11 residues downstream. Most likely this results in the absence of KRIT1 by non-sense mediated decay. CCM prevalence is less than 0.5% of the population with less than 50% of these cases thought to be familial. Therefore, it is important to identify those cases thought to be familial to avoid potential morbidity in the wider family. If a CCM is diagnosed on paediatric neuroimaging it requires a detailed neuro-radiologist reporting with consideration of the family history as younger age of presentation is associated with fewer lesions. The purpose of this report is twofold. First, we suggest including CCM as a differential diagnosis in any individual presenting in status, if it is associated with a positive family history and supporting imaging evidence. Second, as Clinical Genetics becomes mainstreamed throughout other specialties, it is important to emphasis the art of obtaining a detailed family history not only for aiding in the diagnosis in the patient but also for the potential sequellae for the wider family and genetic counseling.
Monosomy 5p and trisomy 12p in a boy with familial balanced translocation
Clinical Dysmorphology, 2006
We report on a boy with monosomy 5p involving the Cri-du-Chat critical region and trisomy 12p det... more We report on a boy with monosomy 5p involving the Cri-du-Chat critical region and trisomy 12p detected by subtelomere study. Familial studies showed that the boy's mother and paternal grandfather had a balanced reciprocal translocation between the short arm of chromosomes 5 and 12. The boy had an overlap of features of both chromosomal conditions, even though the Cri-du-Chat phenotype was more prominent.
A case of Fryns syndrome without diaphragmatic hernia and review of the literature
Clinical Dysmorphology, 2004
We report on a child with Fryns syndrome who showed a characteristic coarse hirsute facial appear... more We report on a child with Fryns syndrome who showed a characteristic coarse hirsute facial appearance, bilateral cleft lip and palate, cardiac and renal anomalies, dilated bowel and distal limb abnormalities. However, diaphragmatic hernia, which is considered a cardinal feature in this condition, was absent in our patient. The parents were consanguineous supporting autosomal recessive inheritance.
Transcription Factor 4 and Myocyte Enhancer Factor 2C mutations are not common causes of Rett syndrome
American Journal of Medical Genetics Part A, 2012
The systematic screening of Rett syndrome (RTT) patients for pathogenetic sequence variations has... more The systematic screening of Rett syndrome (RTT) patients for pathogenetic sequence variations has focused on three genes that have been associated with RTT or related clinical phenotypes, namely MECP2, CDKL5, and FOXG1. More recently, it has been suggested that phenotypes associated with TCF4 and MEF2C mutations may represent a form of RTT.Here we report on the screening of the TCF4 and MEF2C genes in a cohort of 81 classical, atypical, and incomplete atypical RTT patients harboring no known mutations in MECP2, CDKL5, and FOXG1 genes. No pathogenetic sequence variations were identified in the MEF2C gene in our cohort. However, a frameshift mutation in TCF4 was identified in a patient with a clinical diagnosis of “variant” RTT, in whom the clinical evolution later raised the possibility of Pitt–Hopkins syndrome. Although our results suggest that these genes are not commonly associated with RTT, we note the clinical similarity between RTT and Pitt–Hopkins syndrome, and suggest that RT...
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Papers by Pradeep Vasudevan