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1.
Am J Hum Genet ; 111(8): 1605-1625, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39013458

ABSTRACT

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 9 , Craniofacial Abnormalities , DNA Methylation , Genetic Association Studies , Histone-Lysine N-Methyltransferase , Intellectual Disability , Phenotype , Humans , Histone-Lysine N-Methyltransferase/genetics , Craniofacial Abnormalities/genetics , Intellectual Disability/genetics , Chromosomes, Human, Pair 9/genetics , DNA Methylation/genetics , Female , Male , Child , Child, Preschool , Histocompatibility Antigens/genetics , Adolescent , Heart Defects, Congenital/genetics , Haploinsufficiency/genetics , Mutation
2.
Am J Hum Genet ; 111(8): 1626-1642, 2024 Aug 08.
Article in English | MEDLINE | ID: mdl-39013459

ABSTRACT

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.


Subject(s)
Abnormalities, Multiple , Chromosome Deletion , Chromosomes, Human, Pair 9 , Craniofacial Abnormalities , DNA Methylation , DNA-Binding Proteins , Face , Hematologic Diseases , Intellectual Disability , Neurodevelopmental Disorders , Vestibular Diseases , Humans , Abnormalities, Multiple/genetics , Vestibular Diseases/genetics , Intellectual Disability/genetics , Face/abnormalities , Face/pathology , DNA-Binding Proteins/genetics , Male , Female , Hematologic Diseases/genetics , Neurodevelopmental Disorders/genetics , Craniofacial Abnormalities/genetics , Chromosomes, Human, Pair 9/genetics , Child , DNA Methylation/genetics , Child, Preschool , Neoplasm Proteins/genetics , Adolescent , Hypertrichosis/genetics , Mutation , Failure to Thrive/genetics , Histone-Lysine N-Methyltransferase/genetics , Heart Defects, Congenital
3.
Hum Mol Genet ; 32(22): 3123-3134, 2023 11 03.
Article in English | MEDLINE | ID: mdl-37166351

ABSTRACT

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.


Subject(s)
Chromatin , Neurodevelopmental Disorders , Humans , Chromatin/genetics , DNA Methylation/genetics , Mutation , Neurodevelopmental Disorders/genetics , Genetic Association Studies , Codon
4.
Am J Hum Genet ; 109(7): 1217-1241, 2022 07 07.
Article in English | MEDLINE | ID: mdl-35675825

ABSTRACT

GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.


Subject(s)
Neurodevelopmental Disorders , Receptors, AMPA , Cohort Studies , Heterozygote , Humans , Mutation, Missense , Neurodevelopmental Disorders/genetics , Receptors, AMPA/genetics
5.
Hum Mol Genet ; 31(3): 440-454, 2022 02 03.
Article in English | MEDLINE | ID: mdl-34505148

ABSTRACT

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.


Subject(s)
F-Box Proteins , Intellectual Disability , Neurodevelopmental Disorders , F-Box Proteins/genetics , HEK293 Cells , HeLa Cells , Humans , Intellectual Disability/genetics , Mutation, Missense/genetics , Neurodevelopmental Disorders/genetics , Protein-Arginine N-Methyltransferases/genetics
6.
Am J Hum Genet ; 107(6): 1157-1169, 2020 12 03.
Article in English | MEDLINE | ID: mdl-33159883

ABSTRACT

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.


Subject(s)
Chromosome Duplication , Gene Dosage , Intellectual Disability/genetics , Ubiquitin-Protein Ligases/genetics , X Chromosome Inactivation , Adolescent , Australia , Child , Child, Preschool , Face , Female , Hemizygote , Heterozygote , Humans , Male , Middle Aged , Monocarboxylic Acid Transporters/genetics , Mothers , Mutation, Missense , Nerve Tissue Proteins/genetics , Pedigree , Phenotype , Symporters/genetics , Ubiquitin-Protein Ligases/metabolism , Young Adult
7.
Am J Hum Genet ; 106(6): 830-845, 2020 06 04.
Article in English | MEDLINE | ID: mdl-32442410

ABSTRACT

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Craniosynostoses/genetics , Neurodevelopmental Disorders/genetics , Osteochondroma/genetics , SOXD Transcription Factors/genetics , Active Transport, Cell Nucleus , Adolescent , Amino Acid Sequence , Base Sequence , Brain/embryology , Brain/growth & development , Brain/metabolism , Child , Child, Preschool , Computer Simulation , Female , Genomic Structural Variation/genetics , Humans , Infant , Male , Mutation, Missense , Neurodevelopmental Disorders/diagnosis , RNA-Seq , SOXD Transcription Factors/chemistry , SOXD Transcription Factors/metabolism , Syndrome , Transcription, Genetic , Transcriptome , Translocation, Genetic/genetics
8.
Am J Hum Genet ; 104(4): 709-720, 2019 04 04.
Article in English | MEDLINE | ID: mdl-30905399

ABSTRACT

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.


Subject(s)
Cyclin-Dependent Kinase 8/genetics , Developmental Disabilities/genetics , Mediator Complex/genetics , Mutation, Missense , Brain/abnormalities , Child , Child, Preschool , Cyclin C/genetics , Cyclin-Dependent Kinases/genetics , Exome , Female , Heart Defects, Congenital/genetics , Heterozygote , Humans , Infant , Intellectual Disability/genetics , Male , Mutation , Phenotype , Phosphorylation , Syndrome
9.
Am J Med Genet A ; 188(3): 867-877, 2022 03.
Article in English | MEDLINE | ID: mdl-34894057

ABSTRACT

SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.


Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Autism Spectrum Disorder/genetics , Child , Female , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , NAV1.2 Voltage-Gated Sodium Channel/genetics , Phenotype , Seizures/genetics
10.
Dev Med Child Neurol ; 64(1): 14-22, 2022 01.
Article in English | MEDLINE | ID: mdl-34423423

ABSTRACT

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.


Subject(s)
Brain/abnormalities , Counseling , Nervous System Malformations/diagnostic imaging , Parents/psychology , Prenatal Diagnosis , Emotions , Female , Humans , Pregnancy
11.
Dev Med Child Neurol ; 64(1): 23-39, 2022 01.
Article in English | MEDLINE | ID: mdl-34482539

ABSTRACT

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.


Subject(s)
Brain/abnormalities , Nervous System Malformations/diagnostic imaging , Prenatal Diagnosis , Counseling , Female , Humans , Parents , Pregnancy
12.
Am J Med Genet A ; 182(9): 2037-2048, 2020 09.
Article in English | MEDLINE | ID: mdl-32710489

ABSTRACT

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.


Subject(s)
Genetic Predisposition to Disease , Histone-Lysine N-Methyltransferase/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Tubulin/genetics , Child , Child, Preschool , Codon/genetics , Epigenesis, Genetic/genetics , Female , Genetic Association Studies , Humans , Infant , Intellectual Disability/pathology , Loss of Function Mutation/genetics , Male , Mutation, Missense , Nervous System Malformations/genetics , Nervous System Malformations/pathology , Neurodevelopmental Disorders/physiopathology
13.
Epilepsia ; 61(1): e1-e6, 2020 01.
Article in English | MEDLINE | ID: mdl-31849043

ABSTRACT

Pyridoxine-dependent epilepsy (PDE) is a genetic metabolic disease caused by inborn errors affecting vitamin B6 metabolism, which typically presents with neonatal seizures resistant to antiepileptic drugs (AEDs). Treatment with pyridoxine terminates seizures and prevents neurological decline. We describe a case in which the diagnosis was established at the age of 22 years. Birth and development were normal, but there was a history of three isolated tonic-clonic seizures during childhood and adolescence. At the age of 18 years, she developed frequent focal motor seizures, many evolving into tonic-clonic seizures. Electroencephalography identified a focus in the posterior right hemisphere, but magnetic resonance imaging of the brain was normal. Over the next 3 years, she was hospitalized with uncontrolled seizures on six occasions and spent a total of 121 days in intensive care. The seizures proved resistant to 12 different AEDs. Exome sequencing revealed two pathogenic mutations in ALDH7A1. Since starting on pyridoxine 50 mg once daily, she has been seizure-free, all AEDs have been withdrawn, and cognition has improved to premorbid levels. This case illustrates the importance of considering PDE in drug-resistant epilepsy in adults.


Subject(s)
Epilepsy/diagnosis , Status Epilepticus/genetics , Adolescent , Age of Onset , Aldehyde Dehydrogenase/genetics , Epilepsy/complications , Epilepsy/genetics , Female , Humans , Mutation , Pyridoxine/deficiency , Pyridoxine/therapeutic use , Status Epilepticus/diagnosis , Status Epilepticus/drug therapy , Young Adult
14.
Am J Med Genet A ; 179(9): 1884-1894, 2019 09.
Article in English | MEDLINE | ID: mdl-31313512

ABSTRACT

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.


Subject(s)
Dwarfism/genetics , Multienzyme Complexes/genetics , Musculoskeletal Abnormalities/genetics , Osteochondrodysplasias/genetics , Sulfate Adenylyltransferase/genetics , Adolescent , Adult , Child , Child, Preschool , Dwarfism/diagnostic imaging , Dwarfism/physiopathology , Female , Genes, Recessive/genetics , Genetic Predisposition to Disease , Homozygote , Humans , Infant , Infant, Newborn , Male , Musculoskeletal Abnormalities/diagnostic imaging , Musculoskeletal Abnormalities/physiopathology , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/physiopathology , Pedigree , Radiography , Spine/diagnostic imaging , Spine/physiopathology , Exome Sequencing , Young Adult
15.
J Med Genet ; 55(1): 28-38, 2018 01.
Article in English | MEDLINE | ID: mdl-29021403

ABSTRACT

INTRODUCTION: Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. METHODS: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS: Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. CONCLUSIONS: These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.


Subject(s)
CDC2 Protein Kinase/chemistry , CDC2 Protein Kinase/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Mutation/genetics , Adolescent , Child , Conserved Sequence , Female , Heterozygote , Humans , Male , Models, Molecular , Mutation, Missense/genetics , Protein Domains , Syndrome , Thermodynamics
16.
Hum Mutat ; 39(1): 103-113, 2018 01.
Article in English | MEDLINE | ID: mdl-29024177

ABSTRACT

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.


Subject(s)
Filamins/genetics , Genetic Association Studies , Genetic Heterogeneity , Loss of Function Mutation , Phenotype , Transcription, Genetic , Adolescent , Brain/abnormalities , Brain/diagnostic imaging , Child , Conserved Sequence , DNA Mutational Analysis , Female , Filamins/chemistry , Filamins/metabolism , Gastrointestinal Tract/metabolism , Gene Expression , Humans , Magnetic Resonance Imaging , Male , Muscle, Smooth/metabolism , Protein Isoforms , Young Adult
17.
Am J Hum Genet ; 96(3): 462-73, 2015 Mar 05.
Article in English | MEDLINE | ID: mdl-25683120

ABSTRACT

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).


Subject(s)
Contracture/genetics , Extremities/physiopathology , Face/abnormalities , Muscle Hypotonia/genetics , Sodium Channels/genetics , Arthrogryposis/genetics , Craniofacial Dysostosis/genetics , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Exome , Female , Gene Frequency , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Infant , Ion Channels , Male , Membrane Proteins , Mutation, Missense , Sodium Channels/metabolism
18.
Neurogenetics ; 18(2): 111-117, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28229249

ABSTRACT

We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.


Subject(s)
Adenylyl Cyclases/genetics , Dyskinesias/genetics , Dystonic Disorders/genetics , Adolescent , Adult , Child, Preschool , Dyskinesias/complications , Dystonic Disorders/complications , Family , Female , Humans , Middle Aged , Mutation, Missense , Pedigree , Phenotype
19.
Am J Med Genet A ; 170(6): 1556-63, 2016 06.
Article in English | MEDLINE | ID: mdl-26940150

ABSTRACT

Proteoglycans are components of the extracellular matrix with diverse biological functions. Defects in proteoglycan synthesis have been linked to several human diseases with common features of short stature, hypermobility, joint dislocations, and skeletal dysplasia. B4GALT7 encodes galactosyltransferase-I that catalyzes the addition of a galactose moiety to a xylosyl group in the tetrasaccharide linker of proteoglycans. Mutations in this gene have been associated with the rare progeroid form of Ehlers Danlos syndrome and in addition more recently found to underlie Larsen of Reunion Island syndrome. Nine individuals have been reported with a diagnosis of the progeroid form of Ehlers Danlos syndrome, four of whom have had molecular characterization showing homozygous or compound heterozygous mutations in B4GALT7. We report two newly described patients with compound heterozygous mutations in B4GALT7, and show that the six individuals with confirmed mutations do not have the progeroid features described in the original five patients with a clinical diagnosis of the progeroid form of Ehlers Danlos syndrome. We suggest that galactosyltransferase-I deficiency does not cause the progeroid form of Ehlers Danlos syndrome, but instead results in a clinically recognizable syndrome comprising short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia. This group of syndromic patients are on a phenotypic spectrum with individuals who have Larsen of Reunion Island syndrome, although the key features of osteopenia, fractures and hypermetropia have not been reported in patients from Reunion Island. © 2016 Wiley Periodicals, Inc.


Subject(s)
Galactosyltransferases/genetics , Genetic Association Studies , Mutation , Phenotype , Amino Acid Substitution , Bone Density , Codon , Echocardiography , Ehlers-Danlos Syndrome/diagnosis , Ehlers-Danlos Syndrome/genetics , Facies , Female , Humans , Infant , Infant, Newborn , Male , Radiography , Syndrome
20.
Am J Med Genet A ; 170(11): 2835-2846, 2016 11.
Article in English | MEDLINE | ID: mdl-27667800

ABSTRACT

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Tooth Abnormalities/diagnosis , Tooth Abnormalities/genetics , Chromosome Deletion , Chromosomes, Human, Pair 16 , Comparative Genomic Hybridization , Facies , Female , Humans , Male , Phenotype , Repressor Proteins/genetics
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