Publications by authors named "Julie R Jones"

50 Publications

Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation.

Mol Genet Metab 2021 01 17;132(1):27-37. Epub 2020 Oct 17.

Mayo Clinic, Department of Clinical Genomics, Rochester, MN, USA; Mayo Clinic, Department of Laboratory of Medical Pathology, Rochester, MN, USA.

Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death. We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting. His clinical presentation was much less severe than that of the three previously described patients. This is the second report on this ultra-rare disorder. Here we review the characteristics of previously reported individuals with a defect in the DPM complex while expanding the clinical phenotype of DPM2-Congenital Disorders of Glycosylation. In addition, we offer further insights into the pathomechanism of DPM2-CDG disorder by introducing glycomics and lipidomics analysis.
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http://dx.doi.org/10.1016/j.ymgme.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855207PMC
January 2021

Filling in the gaps on FILS syndrome: A case report and literature review.

Pediatr Dermatol 2020 Sep 23;37(5):915-917. Epub 2020 Jul 23.

Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA.

FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature) is a rare autosomal recessive disorder caused by pathogenic alterations in the POLE gene leading to multisystemic manifestations, including poorly characterized skin findings. We report a child with a homozygous variant, c.100C > T (p.Arg34Cys), in POLE and features consistent with poikiloderma, expanding the dermatologic signs associated with this rare disorder. Additionally, we review reported cases of FILS syndrome, discuss possible pathomechanisms for our patient's presentation, and consider implications for management.
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http://dx.doi.org/10.1111/pde.14274DOI Listing
September 2020

Fatal hyperkeratosis syndrome in four siblings due to dolichol kinase deficiency.

Am J Med Genet A 2020 06 6;182(6):1421-1425. Epub 2020 Apr 6.

Greenwood Genetic Center, Greenwood, South Carolina, USA.

A diagnostic journey began in 1966 when a male was born with a lethal hyperkeratosis of undetermined etiology, only to be followed by three additional siblings with the same unknown disorder. All four siblings had unique circumferential skin constrictions on all of their digits. They died within 5 days after birth with no diagnosis or etiology established. The first author (BDH) maintained notes, partial medical records, photographs, and comments about one autopsy report. This information was regularly revisited in the hope of finding a literature match, but no etiological diagnosis was forthcoming. However, in 2017, Rush et al. reported two siblings with similar phenotype in whom they found dolichol kinase deficiency (DOLK). Ultimately, our family was relocated and DNA isolated from the pathology slides of the third affected infant showed compound heterozygous pathogenic variants in the DOLK gene. The variants were in trans, with different missense variants from the mother and father. This 52-year diagnostic pursuit, culminated in an answer that gave the family an explanation for their losses.
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http://dx.doi.org/10.1002/ajmg.a.61574DOI Listing
June 2020

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.

Hum Genet 2020 Apr 13;139(4):483-498. Epub 2020 Feb 13.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.
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http://dx.doi.org/10.1007/s00439-019-02105-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078146PMC
April 2020

BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder.

Hum Mutat 2020 05 7;41(5):921-925. Epub 2020 Feb 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.
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http://dx.doi.org/10.1002/humu.23992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262739PMC
May 2020

Whole-Genome and Segmental Homozygosity Confirm Errors in Meiosis as Etiology of Struma Ovarii.

Cytogenet Genome Res 2020 20;160(1):2-10. Epub 2019 Dec 20.

Strumae ovarii are neoplasms composed of normal-appearing thyroid tissue that occur within the ovary and rarely spread to extraovarian sites. A unique case of struma ovarii with widespread dissemination detected 48 years after removal of a pelvic dermoid provided the opportunity to reexamine the molecular nature of this form of neoplasm. One tumor, from the heart, consisting of benign thyroid tissue was found to have whole-genome homozygosity. Another tumor from the right mandible composed of malignant-appearing thyroid tissue showed whole-genome homozygosity and a deletion of 7p, presumably the second hit that transformed it into a cancerous tumor. Specimens from 2 other cases of extraovarian struma confined to the abdomen and 8 of 9 cases of intraovarian struma showed genome-wide segmental homozygosity. These findings confirm errors in meiosis as the origin of struma ovarii. The histological and molecular findings further demonstrate that even when outside the ovary, strumae ovarii can behave nonaggressively until they receive a second hit, thereafter behaving like cancer.
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http://dx.doi.org/10.1159/000504908DOI Listing
April 2020

Redefining the Etiologic Landscape of Cerebellar Malformations.

Am J Hum Genet 2019 09 29;105(3):606-615. Epub 2019 Aug 29.

Genetic Services, Kaiser Permanente Washington, Seattle, WA 98112, USA.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731369PMC
September 2019

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Hum Mutat 2020 01 14;41(1):150-168. Epub 2019 Nov 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.
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http://dx.doi.org/10.1002/humu.23902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953250PMC
January 2020

Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features.

Am J Med Genet A 2019 07 23;179(7):1276-1286. Epub 2019 May 23.

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.
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http://dx.doi.org/10.1002/ajmg.a.61173DOI Listing
July 2019

Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?

J Hum Genet 2019 Jun 11;64(6):561-572. Epub 2019 Mar 11.

Greenwood Genetic Center, Greenwood, SC, 29646, USA.

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.
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http://dx.doi.org/10.1038/s10038-019-0585-5DOI Listing
June 2019

A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes.

Hum Mol Genet 2019 05;28(9):1548-1560

Greenwood Genetic Center, Greenwood, SC, USA.

Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) are related heterotetrameric complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully assembled GARP and EARP complexes. Likely because of this deficiency, the patient's fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient's fibroblasts exhibits swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.
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http://dx.doi.org/10.1093/hmg/ddy423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489419PMC
May 2019

The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.

Hum Mutat 2018 12 19;39(12):2008-2024. Epub 2018 Sep 19.

Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.

The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.
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http://dx.doi.org/10.1002/humu.23647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240363PMC
December 2018

A Rare De Novo Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation.

Biology (Basel) 2018 May 24;7(2). Epub 2018 May 24.

J. C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA.

Deletions and mutations involving the Retinoic Acid Induced 1 () gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo gene mutation, c.3440G > A (p.R1147Q). We functionally characterized the RAI1 p.R1147Q mutant protein. The mutation, located near the nuclear localization signal, had no effect on the subcellular localization of the mutant protein. However, similar to previously reported RAI1 missense mutations in SMS patients, the RAI1 p.R1147Q mutant protein showed a significant deficiency in activating in vivo transcription of a reporter gene driven by a BDNF (brain-derived neurotrophic factor) intronic enhancer. In addition, expression of other genes associated with neurobehavioral abnormalities and/or neurodevelopmental disorders were found to be altered in this patient. These results suggest a likely contribution of RAI1, either alone or in combination of other factors, to social behavior and reinforce the gene as a candidate gene in patients with autistic manifestations or social behavioral abnormalities.
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http://dx.doi.org/10.3390/biology7020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023015PMC
May 2018

Forkhead box C1 gene variant causing glaucoma and small vessel angiopathy can mimic multiple sclerosis.

Mult Scler Relat Disord 2018 May 21;22:157-160. Epub 2018 Apr 21.

Greenwood Genetic Center, Greenwood, SC 29646, USA.

A 34-year old Caucasian female was initially diagnosed with multiple small-vessel strokes at age 20 years which were etiologically classified as secondary to anti-phospholipid antibody syndrome (APS) although she had no history or laboratory data to suggest APS. Based on her MRI of brain findings, one of her neurologists was concerned she could have multiple sclerosis (MS) and hence the patient was referred to our clinic for further evaluation. The patient's MRI of brain showed confluent lesions in the periventricular and juxta-cortical lesions that fulfil 2017 McDonald criteria for dissemination in space. She had no symptoms other than occasional, mild headaches and had no findings to suggest clinically isolated syndrome (CIS) or MS; additionally, her cerebrospinal fluid analysis was unremarkable. Past history showed that she had undergone surgery for glaucoma, and subsequently developed bilateral sensorineural hearing loss in the third decade that was diagnosed as Meniere's disease. Her family history revealed that her son had dysmorphic facies and was small for age. He had a bifid uvula, bilaterally duplicated thumbs and scoliosis. Additionally, he had hypertelorism, a wide forehead and flattening of mid-face. Due to his complex medical presentation, whole exome sequencing (WES) was performed that revealed a maternally inherited heterozygous pathogenic frameshift in the FOXC1 gene. Genotyping of the mother showed the FOXC1 gene variant and adds to the growing list of differential diagnoses that may mimic MS in the context of radiological changes involving cerebral small vessels. This is the first report of a FOXC1 gene variant presenting with radiological features that can erroneously be interpreted as being consistent with MS.
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http://dx.doi.org/10.1016/j.msard.2018.04.004DOI Listing
May 2018

Ovotesticular Disorder of Sex Development (Ovotestis) in Simpson-Golabi-Behmel Syndrome: Expansion of the Clinical Spectrum.

Pediatr Dev Pathol 2019 Jan-Feb;22(1):70-74. Epub 2018 Apr 13.

1 Department of Pathology, Women and Infants Hospital, Providence, Rhode Island.

Simpson-Golabi-Behmel syndrome type I (SGBS, OMIM312870), caused by defects of the GPC3 and GPC4 genes on chromosome Xq26, is an X-linked recessive macrosomia/multiple congenital anomaly disorder characterized by somatic overgrowth, coarse facial features, variable congenital anomalies, increased tumor risk, and mild-to-moderate neurodevelopmental anomalies. We report the postmortem findings in 3 second-trimester male siblings with SGBS who displayed ambiguous genitalia (in all 3) and gonadal dysgenesis (ovotestis) (in 1), thus expanding the SGBS spectrum to include these disorders of sex development.
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http://dx.doi.org/10.1177/1093526618770327DOI Listing
March 2019

Transgenerational Inheritance of Familial Lipomyelomeningocele.

J Child Neurol 2017 Dec;32(14):1118-1122

4 Greenwood Genetic Center, Greenwood, SC, USA.

Lipomyelomeningocele is a type of neural tube defect characterized by lipomatous tissue causing a defect in the vertebrae, infiltrating the dura, and tethering the spinal cord. Despite significant neurologic consequences, the underlying etiology remains poorly understood. We present a father and son with remarkably similar presentations of lipomyelomeningocele. Genetic testing did not reveal an underlying cause but whole exome sequencing identified variants in the ARHGAP29 and RADIL genes in the proband and his affected father. Genetic analyses of asymptomatic family members revealed several carriers of the ARHGAP29 or RADIL variants, but only the proband and his father carried both variants, suggesting a possible shared genetic mechanism. Rare cases of siblings affected with lipomyelomeningocele have suggested the possibility of autosomal recessive or germline mosaicism. We present the first documented cases of transgenerational lipomyelomeningocele with important implications for family counseling about the recurrence of lipomyelomeningocele.
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http://dx.doi.org/10.1177/0883073817736701DOI Listing
December 2017

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.

Am J Hum Genet 2017 Sep;101(3):466-477

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address:

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.
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http://dx.doi.org/10.1016/j.ajhg.2017.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591022PMC
September 2017

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

Orphanet J Rare Dis 2017 06 28;12(1):121. Epub 2017 Jun 28.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

Background: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.

Results: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.

Conclusions: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.
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http://dx.doi.org/10.1186/s13023-017-0672-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490223PMC
June 2017

encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

J Med Genet 2017 07 4;54(7):460-470. Epub 2017 Apr 4.

Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands.

Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of encephalopathy and explored potential prospects of personalised medicine.

Methods: Data of 48 individuals with de novo variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.

Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.

Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
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http://dx.doi.org/10.1136/jmedgenet-2016-104509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656050PMC
July 2017

Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound.

Am J Med Genet A 2017 May 20;173(5):1219-1225. Epub 2017 Mar 20.

Greenwood Genetic Center, Greenwood, South Carolina.

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.
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http://dx.doi.org/10.1002/ajmg.a.38144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515470PMC
May 2017

Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort.

Genes (Basel) 2016 Nov 9;7(11). Epub 2016 Nov 9.

Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA.

Most histone methyltransferases (HMTase) harbor a predicted Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain, which transfers a methyl group to a lysine residue in their substrates. Mutations of the SET domains were reported to cause intellectual disability syndromes such as Sotos, Weaver, or Kabuki syndromes. Sotos syndrome is an overgrowth syndrome with intellectual disability caused by haploinsufficiency of the nuclear receptor binding SET domain protein 1 () gene, an HMTase at 5q35.2-35.3. Here, we analyzed in 34 Brazilian Sotos patients and identified three novel and eight known mutations. Using protein modeling and bioinformatic approaches, we evaluated the effects of one novel (I2007F) and 21 previously reported missense mutations in the SET domain. For the I2007F mutation, we observed conformational change and loss of structural stability in Molecular Dynamics (MD) simulations which may lead to loss-of-function of the SET domain. For six mutations near the ligand-binding site we observed in simulations steric clashes with neighboring side chains near the substrate S-Adenosyl methionine (SAM) binding site, which may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the missense mutations in the SET domain in Sotos syndrome. mutations were identified in only 32% of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome.
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http://dx.doi.org/10.3390/genes7110096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126782PMC
November 2016

A novel familial autosomal dominant mutation in ARID1B causing neurodevelopmental delays, short stature, and dysmorphic features.

Am J Med Genet A 2016 12 29;170(12):3313-3318. Epub 2016 Aug 29.

Clinical Genetics, Greenwood Genetic Center, Greenwood, South Carolina.

Recent studies have identified mutations in the ARID1B gene responsible for neurodevelopmental delays, intellectual disability, growth delay, and dysmorphic features. ARID1B encodes a subunit of the BAF chromatin-remodeling complex, and mutations in multiple components of the BAF complex have been implicated as causes of Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, and non-syndromic intellectual disability. The majority of documented pathogenic ARID1B mutations to date have arisen in a sporadic, de novo manner with no reports of inheritance of a pathogenic mutation from an affected parent. We describe here two patients (a 21-year-old female and her 21-month-old son) with a novel frameshift mutation in ARID1B inherited in an autosomal dominant fashion in the affected offspring. Both patients presented with neurodevelopmental delays, growth delay, and dysmorphic features including prominent nose with full nasal tip, long philtrum, and high-arched palate. Exome sequencing analysis in the female patient demonstrated a heterozygous deletion of nucleotide 1259 of the ARID1B gene (c.1259delA) resulting in a frameshift and creation of a premature stop codon. Further family testing by targeted Sanger sequencing confirmed that this arose as a de novo mutation in the mother and was passed on to her affected son. The clinical features of both patients are felt to be consistent with an ARID1B-related disorder. To our knowledge, this is the first report of a pathogenic mutation in ARID1B being passed from an affected parent to their offspring. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37945DOI Listing
December 2016

A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.

BMC Neurol 2016 Aug 9;16:132. Epub 2016 Aug 9.

Department of Obstetrics & Gynecology, Section of Reproductive Endocrinology, Infertility & Genetics, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.

Background: Among the 21 annotated genes at Xq22.2, PLP1 is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability. Using an atypical microdeletion, which does not encompass PLP1, we implicate a novel gene GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.

Case Presentation: We report a female patient (DGDP084) with a de novo Xq22.2 microdeletion of at least 110 kb presenting with intellectual disability, motor delay, behavioral problems and craniofacial anomalies. While her phenotypic features such as cognitive impairment and motor delay show overlap with Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations at Xq22.2, this gene is not included in our patient's microdeletion and is not dysregulated by a position effect. Because the microdeletion encompasses only three genes, GLRA4, MORF4L2 and TCEAL1, we investigated their expression levels in various tissues by RT-qPCR and found that all three genes were highly expressed in whole human brain, fetal brain, cerebellum and hippocampus. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084's family, however, only GLRA4 transcripts were reduced in the female patient compared to her healthy mother. This suggests that GLRA4 is the plausible candidate gene for cognitive impairment, behavioral problems and craniofacial anomalies observed in DGDP084. Importantly, glycine receptors mediate inhibitory synaptic transmission in the brain stem as well as the spinal cord, and are known to be involved in syndromic intellectual disability.

Conclusion: We hypothesize that GLRA4 is involved in intellectual disability, behavioral problems and craniofacial anomalies as the second gene identified for X-linked syndromic intellectual disability at Xq22.2. Additional point mutations or intragenic deletions of GLRA4 as well as functional studies are needed to further validate our hypothesis.
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http://dx.doi.org/10.1186/s12883-016-0642-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979147PMC
August 2016

De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features.

Cold Spring Harb Mol Case Stud 2016 Jan;2(1):a000661

Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;; Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.

We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore-microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.
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http://dx.doi.org/10.1101/mcs.a000661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849844PMC
January 2016

CHD8 intragenic deletion associated with autism spectrum disorder.

Eur J Med Genet 2016 Apr 26;59(4):189-94. Epub 2016 Feb 26.

Greenwood Genetic Center, Greenwood, SC, 29646, USA.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are highly heritable. De novo genomic alterations are considered an important cause of autism spectrum disorders. Recent research has shown that de novo loss-of-function mutations in the chromodomain helicase DNA-binding protein 8 (CHD8) gene are associated with an increased risk of ASD. We describe a single case of an intragenic deletion of exons 26-28 in the CHD8 gene in a patient with autism and global developmental delay. Our clinical case supports the hypothesis that CHD8 may play a central role in neuronal cell development and ASD risk.
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http://dx.doi.org/10.1016/j.ejmg.2016.02.010DOI Listing
April 2016

Lessons from a pair of siblings with BPAN.

Eur J Hum Genet 2016 07 18;24(7):1080-3. Epub 2015 Nov 18.

Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.
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http://dx.doi.org/10.1038/ejhg.2015.242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070893PMC
July 2016

Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin-Lowry syndrome.

Gene 2016 Jan 20;575(1):42-7. Epub 2015 Aug 20.

Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA. Electronic address:

Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant disorder characterized by diverse phenotypes including intellectual disability, facial and digital anomalies. Loss-of-function mutations in the Ribosomal Protein S6 Kinase Polypeptide 3 (RPS6KA3) gene have been shown to be responsible for CLS. Among the large number of mutations, however, no exonic mutation causing exon skipping has been described. Here, we report a male patient with CLS having a novel mutation at the 3' end of an exon at a splice donor junction. Interestingly, this nucleotide change causes both a novel missense mutation and partial exon skipping leading to a truncated transcript. These two transcripts were identified by cDNA sequencing of RT-PCR products. In the carrier mother, we found only wildtype transcripts suggesting skewed X-inactivation. Methylation studies confirmed X-inactivation was skewed moderately, but not completely, which is consistent with her mild phenotype. Western blot showed that the mutant RSK2 protein in the patient is expressed at similar levels relative to his mother. Protein modeling demonstrated that the missense mutation is damaging and may alter binding to ATP molecules. This is the first report of exon skipping from an exonic mutation of RPS6KA3, demonstrating that a missense mutation and concomitant disruption of normal splicing contribute to the manifestation of CLS.
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http://dx.doi.org/10.1016/j.gene.2015.08.032DOI Listing
January 2016

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

Eur J Hum Genet 2015 Nov 29;23(11):1482-7. Epub 2015 Apr 29.

Departments of Pediatrics and Genetics, Division of Genetics and Metabolism, University of North Carolina, Chapel Hill, NC, USA.

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.
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http://dx.doi.org/10.1038/ejhg.2015.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613470PMC
November 2015

The historical Coffin-Lowry syndrome family revisited: identification of two novel mutations of RPS6KA3 in three male patients.

Am J Med Genet A 2014 Sep 7;164A(9):2172-9. Epub 2014 Jul 7.

Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.

Coffin-Lowry syndrome (CLS) is a rare X-linked dominant disorder characterized by intellectual disability, craniofacial abnormalities, short stature, tapering fingers, hypotonia, and skeletal malformations. CLS is caused by mutations in the Ribosomal Protein S6 Kinase, 90 kDa, Polypeptide 3 (RPS6KA3) gene located at Xp22.12, which encodes Ribosomal S6 Kinase 2 (RSK2). Here we analyzed RPS6KA3 in three unrelated CLS patients including one from the historical Coffin-Lowry syndrome family and found two novel mutations. To date, over 140 mutations in RPS6KA3 have been reported. However, the etiology of the very first familial case, which was described in 1971 by Lowry with detailed phenotype and coined the term CLS, has remained unknown. More than 40 years after the report, we succeeded in identifying deposited fibroblast cells from one patient of this historic family and found a novel heterozygous 216 bp in-frame deletion, encompassing exons 15 and 16 of RPS6KA3. Drop episodes in CLS patients were reported to be associated with truncating mutations deleting the C-terminal kinase domain (KD), and only one missense mutation and one single basepair duplication involving the C-terminal KD of RSK2 in the patients with drop episode have been reported thus far. Here we report the first in-frame deletion in C-terminal KD of RPS6KA3 in a CLS patient with drop episodes.
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http://dx.doi.org/10.1002/ajmg.a.36488DOI Listing
September 2014