Papers by Suneeta Madan-Khetarpal
55th ESPE Meeting, Aug 19, 2016
List of 520 genes in the intellectual disability panel. (XLSX 17 kb)
CLINICAL/TRANSLATIONAL - Pediatric Endocrinology: Puberty, 2011
npj Genomic Medicine, Dec 7, 2021
The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms... more The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
Genome Medicine, Aug 14, 2017
Background: De novo missense variants in CDK13 have been described as the cause of syndromic cong... more Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.
Case Reports, Jun 9, 2011
There was an error in the dosage recorded in the Summary section of this article. The dosage of c... more There was an error in the dosage recorded in the Summary section of this article. The dosage of carbidopa should have read '37.5 mg once a day' and NOT '37.5 mg four times a day'.
Molecular Genetics & Genomic Medicine
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.
Human Mutation, 2020
KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of ... more KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified 8 additional cases with heterozygous, pathogenic KIF1A variants-ascertained from a local data lake. Our data provide evidence for expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with
Brain
In the field of rare diseases, progress in molecular diagnostics led to the recognition that vari... more In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0–24 years). Most individuals prese...
Genetics in Medicine, 2021
BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical ... more BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes. We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1. We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.
We present an elementary system of axioms for the geometry of Minkowski spacetime. It strikes a b... more We present an elementary system of axioms for the geometry of Minkowski spacetime. It strikes a balance between a simple and streamlined set of axioms and the attempt to give a direct formalization in first-order logic of the standard account of Minkowski spacetime in [Maudlin 2012] and [Malament, unpublished]. It is intended for future use in the formalization of physical theories in Minkowski spacetime. The choice of primitives is in the spirit of [Tarski 1959]: a predicate of betwenness and a four place predicate to compare the square of the relativistic intervals. Minkowski spacetime is described as a four dimensional 'vector space' that can be decomposed everywhere into a spacelike hyperplane-which obeys the Euclidean axioms in [Tarski and Givant, 1999]-and an orthogonal timelike line. The length of other 'vectors' are calculated according to Pythagoras' theorem. We conclude with a Representation Theorem relating models M of our system M 1 that satisfy second order continuity to the mathematical structure xR 4 , η ab y, called 'Minkowski spacetime' in physics textbooks. * We are grateful to John Burgess, Dino Calosi, Harold Hodes and Chris Wüthrich for discussion and comments on parts of this paper.
Genetics in Medicine, 2022
Clinical Genetics, 2020
Meiotic recombination (MR) drives novel combination of alleles and contributes to genomic diversi... more Meiotic recombination (MR) drives novel combination of alleles and contributes to genomic diversity in eukaryotes. In this study, we showed that heat stress (36-38°C) over fertile threshold fully abolished crossover (CO) formation in Arabidopsis. Cytological and genetic studies in wild-type plants, and the syn1 and rad51 mutants suggested that heat stress reduces generation of SPO11-dependent double-strand breaks (DSBs). In support, the abundance of recombinase DMC1, which is required for MR-specific DSB repair, was significantly reduced under heat stress. In addition, we showed that high temperatures induced disassembly and/or instability of ASY4-but not SYN1-mediated chromosome axis. At the same time, ASY1-associated lateral preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
American Journal of Medical Genetics Part A, 2021
Background PHF21A has been associated with intellectual disability and craniofacial anomalies bas... more Background PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results We have identified seven hetero...
permits unrestricted use, distribution, and reproduction in any medium, provided the original wor... more permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We characterized three supernumerary marker chromosomes (SMCs) simultaneously present in a 2-year- and 10-month-old male patient with mental retardation and dysmorphic features. Peripheral blood chromosome analysis revealed two to three SMCs in 25/26 cells analyzed. The remaining one cell had one SMC. Microarray comparative genomic hybridization (aCGH) showed mosaicism for gains of 5q35.3, 15q11.2q13.3, and 18p11.21q11.1 regions. All three gains contain multiple OMIM genes. FISH studies indicated that one of the SMCs is a dicentric ring 15 with two copies of the 15q11.2q13.3 region including SNRPN/UBE3A and two copies of the 5q35.3 region. One of the der(18)s contains the 18 centromere and 18p11.2 regions, while the other der(18) has a signal for the 18 centromere only. The phenotype of the patient is compared with that of patients with tetrasomy 15q11.2q13.3, trisom...
Epilepsia, 2021
CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and... more CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow‐up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
Genome Medicine, 2021
Background With the increasing number of genomic sequencing studies, hundreds of genes have been ... more Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Util...
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Papers by Suneeta Madan-Khetarpal