Publications by authors named "Lindsay B Henderson"

31 Publications

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor.

Hum Mutat 2021 06 15;42(6):685-693. Epub 2021 Apr 15.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.
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http://dx.doi.org/10.1002/humu.24201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162891PMC
June 2021

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.

Orphanet J Rare Dis 2021 03 18;16(1):136. Epub 2021 Mar 18.

Sackler School of Medicine at Tel Aviv University, Tel Aviv, Israel.

Background: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.

Results: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation.

Conclusions: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
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http://dx.doi.org/10.1186/s13023-021-01744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977188PMC
March 2021

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K channelopathies.

Eur J Hum Genet 2021 Sep 16;29(9):1384-1395. Epub 2021 Feb 16.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K conductance, referred to as syndromic neurodevelopmental K channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
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http://dx.doi.org/10.1038/s41431-021-00818-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440610PMC
September 2021

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Am J Med Genet A 2021 05 31;185(5):1366-1378. Epub 2021 Jan 31.

Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
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http://dx.doi.org/10.1002/ajmg.a.62102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048530PMC
May 2021

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

Clin Genet 2021 02 23;99(2):259-268. Epub 2020 Nov 23.

Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.
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http://dx.doi.org/10.1111/cge.13874DOI Listing
February 2021

Monogenic variants in dystonia: an exome-wide sequencing study.

Lancet Neurol 2020 11;19(11):908-918

Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

Funding: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
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http://dx.doi.org/10.1016/S1474-4422(20)30312-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246240PMC
November 2020

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Am J Hum Genet 2020 08 31;107(2):311-324. Epub 2020 Jul 31.

Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413890PMC
August 2020

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 06 21;106(6):830-845. Epub 2020 May 21.

Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

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.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273536PMC
June 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

GeneDx, Gaithersburg, MD, USA.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
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http://dx.doi.org/10.1093/brain/awz379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962909PMC
January 2020

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Brain 2019 10;142(10):2948-2964

Department of Clinical and Experimental Medicine, University of Messina, Sicily.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.
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http://dx.doi.org/10.1093/brain/awz248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763744PMC
October 2019

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Am J Hum Genet 2019 03 28;104(3):542-552. Epub 2019 Feb 28.

Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Montañeses, Buenos Aires 2325, Argentina.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407605PMC
March 2019

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features.

Am J Hum Genet 2018 11 18;103(5):786-793. Epub 2018 Oct 18.

Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address:

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218713PMC
November 2018

Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.

Orphanet J Rare Dis 2018 05 31;13(1):86. Epub 2018 May 31.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Background: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations.

Methods: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature.

Results: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells.

Conclusions: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.
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http://dx.doi.org/10.1186/s13023-018-0825-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048855PMC
May 2018

Recessive mutations in VPS13D cause childhood onset movement disorders.

Ann Neurol 2018 06 10;83(6):1089-1095. Epub 2018 Apr 10.

Department of Pediatrics, Saint Justine University Hospital Center and University of Montreal, Montreal, Canada.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.
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http://dx.doi.org/10.1002/ana.25204DOI Listing
June 2018

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Cell 2018 02;172(5):924-936.e11

Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
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http://dx.doi.org/10.1016/j.cell.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832058PMC
February 2018

Missense variants in the chromatin remodeler are associated with neurodevelopmental disability.

J Med Genet 2018 08 2;55(8):561-566. Epub 2017 Sep 2.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Background: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.

Objectives: To explore whether variants in are associated with a human phenotype.

Methods: We used GeneMatcher to identify other physicians caring for patients with variants in . We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.

Results: Here we describe six heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in .

Conclusions: Our results suggest that variants in can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
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http://dx.doi.org/10.1136/jmedgenet-2017-104759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834353PMC
August 2018

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.

Ann Neurol 2017 Sep;82(3):466-478

Department of Biological Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea.

Objective: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.

Methods: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.

Results: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.

Interpretation: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.
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http://dx.doi.org/10.1002/ana.25032DOI Listing
September 2017

Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.

Eur J Hum Genet 2017 08 17;25(8):946-951. Epub 2017 May 17.

Department of Medical Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.
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http://dx.doi.org/10.1038/ejhg.2017.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567153PMC
August 2017

Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features.

Neurogenetics 2016 07 22;17(3):159-64. Epub 2016 Mar 22.

Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, 10032, NY, USA.

Human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay.
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http://dx.doi.org/10.1007/s10048-016-0479-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907844PMC
July 2016

De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism.

Neurogenetics 2016 Jan 17;17(1):43-9. Epub 2015 Nov 17.

Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.

Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.
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http://dx.doi.org/10.1007/s10048-015-0466-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765493PMC
January 2016

The impact of chromosomal microarray on clinical management: a retrospective analysis.

Genet Med 2014 Sep 13;16(9):657-64. Epub 2014 Mar 13.

1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA [2] Cytogenetics Laboratory, Kennedy Krieger Institute, Baltimore, Maryland, USA [3] Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Purpose: Chromosomal microarray has been widely adopted as the first-tier clinical test for individuals with multiple congenital anomalies, developmental delay, intellectual disability, and autism spectrum disorders. Although chromosomal microarray has been extensively shown to provide a higher diagnostic yield than conventional cytogenetic methods, some health insurers refuse to provide coverage for this test, claiming that it is experimental and does not affect patients' clinical management.

Methods: We retrospectively reviewed the electronic medical records of all patients who had abnormal chromosomal microarray findings reported by our laboratory over a 3-year period and quantified the management recommendations made in response to these results.

Results: Abnormal chromosomal microarray findings were reported for 12.7% of patients (227/1,780). For patients with clinical follow-up notes available, these results had management implications for 54.5% of patients in the entire abnormal cohort (102/187) and for 42.1% of patients referred for isolated neurodevelopmental disorders (16/38). Recommendations included pharmacological treatment, cancer-related screening or exclusion of screening, contraindications, and referrals for further evaluation.

Conclusion: These results empirically demonstrate the clinical utility of chromosomal microarray by providing evidence that management was directly affected for the majority of patients in our cohort with abnormal chromosomal microarray findings.
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http://dx.doi.org/10.1038/gim.2014.18DOI Listing
September 2014

Large ABCA3 and SFTPC deletions resulting in lung disease.

Ann Am Thorac Soc 2013 Dec;10(6):602-7

1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.

Rationale: Mutations in genes encoding proteins important in the function and metabolism of pulmonary surfactant are recognized causes of lung disease. Clinical genetic testing is available for these disorders, but children with phenotypes consistent with surfactant dysfunction and no identifiable mutations in the known causative genes have been reported.

Objectives: To identify the mechanism(s) for lung disease in two children with the phenotype of surfactant dysfunction who had negative testing in clinical laboratories for gene mutations causing surfactant dysfunction.

Methods: Amplicons spanning multiple exons of candidate genes were generated by polymerase chain reaction and sequenced.

Measurements And Main Results: A 4,335-base deletion that included all of exon 12 of the gene encoding member A3 of the adenosine triphosphate-binding cassette transporter was identified in a full-term infant with respiratory failure. A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease.

Conclusions: Large deletions are a cause of surfactant dysfunction disorders and may need to be sought for specifically in children whose phenotypes suggest these syndromes but in whom clinical genetic testing is unrevealing.
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http://dx.doi.org/10.1513/AnnalsATS.201306-170OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960967PMC
December 2013

First trimester diagnosis of holoprosencephaly secondary to a ring chromosome 7.

Case Rep Genet 2013 21;2013:578202. Epub 2013 Feb 21.

Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Holoprosencephaly (HPE) is a developmental defect in humans in which the forebrain fails to completely separate into two hemispheres. We describe a 12 3/7-week-old fetus found on ultrasound evaluation to have features consistent with HPE, including a single anterior ventricle, fused thalami, and a flattened profile. Cytogenetic analysis of chorionic villi revealed a ring chromosome 7 [r(7)]. This uncommon finding has been associated with growth delay, microcephaly, and dermatologic abnormalities. However, both the clinical features and the extent of cytogenetic imbalance of chromosome 7 are variable, and few reported cases of r(7) have been molecularly studied. To our knowledge, this is the first report of a prenatally identified r(7), molecularly characterized using array comparative genomic hybridization.
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http://dx.doi.org/10.1155/2013/578202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594923PMC
March 2013

Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis.

PLoS Genet 2012 15;8(3):e1002580. Epub 2012 Mar 15.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5' to and within the MSRA gene were associated with MI (P = 1.99 × 10(-5) to 1.08 × 10(-6); Bonferroni P = 0.057 to 3.1 × 10(-3)). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53-0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2 × 10(-4)). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr(-/-) and Cftr(-/-)Msra(-/-) mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
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http://dx.doi.org/10.1371/journal.pgen.1002580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305406PMC
September 2012

Genomic changes in gliomas detected using single nucleotide polymorphism array in formalin-fixed, paraffin-embedded tissue: superior results compared with microsatellite analysis.

J Mol Diagn 2011 Sep 2;13(5):541-8. Epub 2011 Jul 2.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Deletion or loss of heterozygosity (LOH) in chromosomes 1p and 19q in oligodendrogliomas (ODGs) have diagnostic, prognostic, and therapeutic implications. Current clinical assays are limited because the probes or primers interrogate only limited genomic segments. We investigated the use of single nucleotide polymorphism (SNP) arrays for identifying genomic changes in gliomas from FFPE tissues. DNA was extracted from FFPE tissues of 30 brain tumor cases (15 ODGs and 15 non-ODGs) and assayed on the Illumina array with 300,000 markers. SNP results were compared with standard short tandem repeat (STR) assays of chromosomes 1p and 19q. Fifteen ODGs had LOH by STR and deletion by array on both 1p and 19q. Ten non-ODGs had no evidence of LOH on 1p and 19q by STR, seven of which had no abnormalities for these chromosomes; three had partial deletions by SNP array. Five non-ODG cases had partial LOH or deletion by both assays. No major discordance was found between SNP array and STR results. Advantages of SNP arrays include no need for an accompanying normal sample, the ability to find small segmental deletions, the potential to distinguish between deletions and copy neutral LOH, and whole-genome screening to allow discovery of new, significant loci. Assessment of genomic changes in routine glioma specimens using SNP arrays is feasible and has great potential as an accurate clinical diagnostic test.
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http://dx.doi.org/10.1016/j.jmoldx.2011.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157617PMC
September 2011

Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients.

Respir Res 2010 Oct 8;11:140. Epub 2010 Oct 8.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF.

Methods: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories.

Results: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile).

Conclusions: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.
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http://dx.doi.org/10.1186/1465-9921-11-140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964615PMC
October 2010

Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis.

Eur J Hum Genet 2010 Jun 13;18(6):680-4. Epub 2010 Jan 13.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.
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http://dx.doi.org/10.1038/ejhg.2009.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874654PMC
June 2010
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