Publications by authors named "Marie T McDonald"

35 Publications

An Unusual Association: Total Anomalous Pulmonary Venous Return and Aortic Arch Obstruction in Patients with Cat Eye Syndrome.

J Pediatr Genet 2021 Mar 20;10(1):35-38. Epub 2020 Jan 20.

Division of Pediatric Cardiology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States.

Cat eye syndrome (CES) is a rare genetic defect, characterized by iris colobomas, preauricular skin tags, and anal malformations. Affecting 1 in 150,000 people, this defect is caused by duplication or triplication of the proximal long (q) arm of chromosome 22. Congenital heart disease is associated with CES. One of the most common heart defects in patients with CES is total anomalous pulmonary venous return (TAPVR). In this article, we reported patients with a rare association of concomitant TAPVR and aortic arch obstruction: one with interrupted aortic arch and the other with coarctation of the aorta with an aberrant right subclavian artery.
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http://dx.doi.org/10.1055/s-0039-1701020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853914PMC
March 2021

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Genet Med 2020 Dec 10. Epub 2020 Dec 10.

Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
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http://dx.doi.org/10.1038/s41436-020-01020-wDOI Listing
December 2020

A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.

Eur J Hum Genet 2021 Feb 8;29(2):271-279. Epub 2020 Sep 8.

Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.
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http://dx.doi.org/10.1038/s41431-020-00717-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868361PMC
February 2021

A pathogenic variant in the SETBP1 hotspot results in a forme-fruste Schinzel-Giedion syndrome.

Am J Med Genet A 2020 08 22;182(8):1947-1951. Epub 2020 May 22.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.

Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, with survival beyond the first decade rare. Germline, de novo heterozygous variants in the SETBP1 gene cause SGS with the pathogenic variants associated with the SGS phenotype missense and confined to exon 4 of the gene, clustered in a four amino acid (12 bp) hotspot in the SKI homologous region of the SETBP1 protein. We report a patient with a de novo I871S variant within the SKI homologous region, which has been associated with the severe phenotype previously; but our patient has fewer features of SGS and a milder course. This is the first report of a forme-fruste phenotype in a patient with a pathogenic variant within the SGS hotspot on the SETBP1 gene and it highlights the importance of considering atypical clinical presentations in the context of severe ultra-rare genetic disorders.
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http://dx.doi.org/10.1002/ajmg.a.61630DOI Listing
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.

Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale, 31000 Toulouse, France. Electronic address:

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

Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses.

Genet Med 2020 Jul 5;22(7):1269-1275. Epub 2020 May 5.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Purpose: Guidelines by professional organizations for assessing variant pathogenicity include the recommendation to utilize biologically relevant transcripts; however, there is variability in transcript selection by laboratories.

Methods: We describe three patients whose genomic results were incorrect, because alternative transcripts and tissue expression patterns were not considered by the commercial laboratories.

Results: In individual 1, a pathogenic coding variant in a brain-expressed isoform of CKDL5 was missed twice on sequencing, because the variant was intronic in the transcripts considered in analysis. In individual 2, a microdeletion affecting KMT2C was not reported on microarray, since deletions of proximal exons in this gene are seen in healthy individuals; however, this individual had a more distal deletion involving the brain-expressed KMT2C isoform, giving her a diagnosis of Kleefstra syndrome. Individual 3 was reported to have a pathogenic variant in exon 10 of OFD1 on exome, but had no typical features of the OFD1-related disorders. Since exon 10 is spliced from the more biologically relevant transcripts of OFD1, it was determined that he did not have an OFD1 disorder.

Conclusion: These examples illustrate the importance of considering alternative transcripts as a potential confounder when genetic results are negative or discordant with the phenotype.
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http://dx.doi.org/10.1038/s41436-020-0781-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335342PMC
July 2020

CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.

Hum Mutat 2020 03 3;41(3):655-667. Epub 2019 Dec 3.

Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio-exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT-1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT-1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients' fibroblasts compared to controls. Our data indicate that biallelic loss-of-function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1-CDG.
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http://dx.doi.org/10.1002/humu.23952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027858PMC
March 2020

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies.

Am J Hum Genet 2019 01;104(1):94-111

Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA. Electronic address:

The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323578PMC
January 2019

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Genet Med 2019 03;21(3):764-765

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.
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http://dx.doi.org/10.1038/s41436-018-0326-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608433PMC
March 2019

Biallelic mutations in FDXR cause neurodegeneration associated with inflammation.

J Hum Genet 2018 Dec 25;63(12):1211-1222. Epub 2018 Sep 25.

Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH, USA, 45229.

Mitochondrial dysfunction lies behind many neurodegenerative disorders, owing largely to the intense energy requirements of most neurons. Such mitochondrial dysfunction may work through a variety of mechanisms, from direct disruption of the electron transport chain to abnormal mitochondrial biogenesis. Recently, we have identified biallelic mutations in the mitochondrial flavoprotein "ferredoxin reductase" (FDXR) gene as a novel cause of mitochondriopathy, peripheral neuropathy, and optic atrophy. In this report, we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy. To investigate the underlying pathogenesis, we examined neurodegeneration in a mouse model. We found that Fdxr mutant mouse brain tissues share pathological changes similar to those seen in patient autopsy material, including increased astrocytes. Furthermore, we show that these abnormalities are associated with increased levels of markers for both neurodegeneration and gliosis, with the latter implying inflammation as a major factor in the pathology of Fdxr mutations. These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment.
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http://dx.doi.org/10.1038/s10038-018-0515-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451867PMC
December 2018

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Genet Med 2019 04 7;21(4):867-876. Epub 2018 Sep 7.

Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.

Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.

Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.

Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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http://dx.doi.org/10.1038/s41436-018-0269-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752285PMC
April 2019

Further evidence for the involvement of in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Cincinnati Children's Hospital Medical Center, Division of Human Genetics, Cincinnati, Ohio 45229, USA.

Recent evidence has implicated in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between and the previously known causative gene accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.
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http://dx.doi.org/10.1101/mcs.a003046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169826PMC
October 2018

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

Hum Mol Genet 2018 07;27(14):2454-2465

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

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.
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http://dx.doi.org/10.1093/hmg/ddy146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030957PMC
July 2018

Hemimegalencephaly with Bannayan-Riley-Ruvalcaba syndrome.

Epileptic Disord 2018 Feb;20(1):30-34

Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, USA.

Hemimegalencephaly is known to occur in Proteus syndrome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan-Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly, developmental delay, athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.
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http://dx.doi.org/10.1684/epd.2018.0954DOI Listing
February 2018

Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".

Am J Hum Genet 2017 Nov;101(5):815-823

Centre Hospitalier Universitaire Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673654PMC
November 2017

Neuro-oculo-cutaneous cavernous hemangiomas: a CCM1 mutation-associated phakomatosis.

J AAPOS 2017 Oct 1;21(5):426-429.e1. Epub 2017 Sep 1.

Department of Ophthalmology, Duke University, Durham, North Carolina; Department of Radiation Oncology, Duke University, Durham, North Carolina; Department of Ophthalmology, Stanford University, Stanford, California. Electronic address:

Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life-threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene.
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http://dx.doi.org/10.1016/j.jaapos.2017.06.012DOI Listing
October 2017

Identification of mutation: clinical use of microarray.

Clin Case Rep 2017 06 10;5(6):980-985. Epub 2017 May 10.

Division of Medical Genetics Department of Pediatrics Duke University Health System Durham North Carolina.

We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis.
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http://dx.doi.org/10.1002/ccr3.914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457984PMC
June 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

De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.

Ann Clin Transl Neurol 2015 Jun 1;2(6):623-35. Epub 2015 May 1.

Department of Neurology, University of California San Francisco, California, 94158.

Objective: To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children.

Methods: Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function.

Results: All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay.

Interpretation: De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.
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http://dx.doi.org/10.1002/acn3.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479523PMC
June 2015

Adult surgical experience with Loeys-Dietz syndrome.

Ann Thorac Surg 2015 Apr 10;99(4):1275-81. Epub 2015 Feb 10.

Department of Surgery, Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Background: Loeys-Dietz syndrome (LDS) results from mutations in receptors for the cytokine transforming growth factor-β leading to aggressive aortic pathology sometimes accompanied by specific phenotypic features including bifid uvula, hypertelorism, cleft palate, and generalized arterial tortuosity. We reviewed our adult surgical experience with LDS in order to validate current recommendations regarding management of this newly described disease.

Methods: All adult (≥ 18 years old) patients with LDS undergoing surgical treatment at a single referral institution from September 1999 to May 2013 were retrospectively reviewed.

Results: Eleven adult LDS patients were identified by clinical criteria and genotyping. Seven (64%) experienced acute type A dissection at some point in their lives. All eventually required aortic root replacement, and 73% required multiple vascular surgical interventions. Over a mean follow-up of 65 ± 49 months, 2.8 cardiovascular procedures per patient were performed. In patients with type A dissection, a mean of 3.4 operations were performed versus 1.8 operations for patients without dissection. Total aortic replacement was required in 5 patients (45%) and 2 (18%) required neurosurgical intervention for cerebrovascular pathology. There was 1 late death from infectious complications, and no deaths from vascular catastrophe.

Conclusions: These results confirm the aggressive nature of LDS aortic pathology. However, the improved survival compared with earlier LDS reports suggest that aggressive treatment strategies may alter outcomes and improve the natural history of this syndrome.
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http://dx.doi.org/10.1016/j.athoracsur.2014.11.021DOI Listing
April 2015

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.

Am J Hum Genet 2013 Apr;92(4):627-31

Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.

The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
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http://dx.doi.org/10.1016/j.ajhg.2013.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617390PMC
April 2013

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Hum Mutat 2013 Jun 12;34(6):801-11. Epub 2013 Apr 12.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
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http://dx.doi.org/10.1002/humu.22313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663886PMC
June 2013

A 137-kb deletion within the Potocki-Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia.

Am J Med Genet A 2013 Jan 13;161A(1):198-202. Epub 2012 Dec 13.

Department of Pathology, University of North Carolina, Chapel Hill, NC, USA.

Potocki-Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency of genes located on the proximal short arm of chromosome 11 (11p11.2p12). Classic features include biparietal foramina, multiple exostoses, profound hypotonia, dysmorphic features, and developmental delay/intellectual disability. Fewer than 40 individuals with PSS have been reported, with variable clinical presentations due in part to disparity in deletion sizes. We report on a boy who presented for initial evaluation at age 13 months because of a history of developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2, which maps within the classically defined PSS interval. This deletion results in haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2, MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting PHF21A have been associated with intellectual disability and craniofacial anomalies similar to those seen in PSS. The identification of this small deletion in a child with developmental delay and hypotonia provides further evidence for the genetic basis of developmental disability and identifies a critical region sufficient to cause hypotonia in this syndrome. Additionally, this case illustrates the utility of high resolution genomic approaches in correlating clinical phenotypes with specific genes in contiguous gene deletion syndromes.
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http://dx.doi.org/10.1002/ajmg.a.35671DOI Listing
January 2013

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

Am J Med Genet A 2012 Sep 27;158A(9):2152-61. Epub 2012 Jul 27.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.
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http://dx.doi.org/10.1002/ajmg.a.35574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429713PMC
September 2012

Clinical application of exome sequencing in undiagnosed genetic conditions.

J Med Genet 2012 Jun 11;49(6):353-61. Epub 2012 May 11.

Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA.

Background: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.

Methods: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.

Results: This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).

Conclusions: This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.
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http://dx.doi.org/10.1136/jmedgenet-2012-100819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375064PMC
June 2012

Further clinical and molecular delineation of the 15q24 microdeletion syndrome.

J Med Genet 2012 Feb 17;49(2):110-8. Epub 2011 Dec 17.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, DC 98195, USA.

Background: Chromosome 15q24 microdeletion syndrome is a rare genomic disorder characterised by intellectual disability, growth retardation, unusual facial morphology and other anomalies. To date, 20 patients have been reported; 18 have had detailed breakpoint analysis.

Aim: To further delineate the features of the 15q24 microdeletion syndrome, the clinical and molecular characterisation of fifteen patients with deletions in the 15q24 region was performed, nearly doubling the number of reported patients.

Methods: Breakpoints were characterised using a custom, high-density array comparative hybridisation platform, and detailed phenotype information was collected for each patient.

Results: Nine distinct deletions with different breakpoints ranging in size from 266 kb to 3.75 Mb were identified. The majority of breakpoints lie within segmental duplication (SD) blocks. Low sequence identity and large intervals of unique sequence between SD blocks likely contribute to the rarity of 15q24 deletions, which occur 8-10 times less frequently than 1q21 or 15q13 microdeletions in our series. Two small, atypical deletions were identified within the region that help delineate the critical region for the core phenotype in the 15q24 microdeletion syndrome.

Conclusion: The molecular characterisation of these patients suggests that the core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a 1.1-Mb critical region. However, genes just distal to the critical region also play an important role in cognition and in the development of characteristic facial features associated with 15q24 deletions. Clearly, deletions in the 15q24 region are variable in size and extent. Knowledge of the breakpoints and size of deletion combined with the natural history and medical problems of our patients provide insights that will inform management guidelines. Based on common phenotypic features, all patients with 15q24 microdeletions should receive a thorough neurodevelopmental evaluation, physical, occupational and speech therapies, and regular audiologic and ophthalmologic screening.
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http://dx.doi.org/10.1136/jmedgenet-2011-100499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261729PMC
February 2012

Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture.

Nat Genet 2010 Nov 3;42(11):1015-20. Epub 2010 Oct 3.

Division of Genetics, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, USA.

Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.
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http://dx.doi.org/10.1038/ng.683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2969850PMC
November 2010

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

Nat Genet 2010 Mar 14;42(3):203-9. Epub 2010 Feb 14.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
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http://dx.doi.org/10.1038/ng.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847896PMC
March 2010

Clinical experience with array CGH: case presentations from nine months of practice.

Am J Med Genet A 2006 Oct;140(19):2050-6

Department of Pediatrics, Division of Clinical Genetics, Duke University Medical Center, Durham, North Carolina 27516, USA.

A total of 124 individuals were tested in the initial 9 months that array CGH technology was offered to clinical genetics patients. In 11 of these patients array CGH identified a previously unsuspected diagnosis. A suspected diagnosis was confirmed in three patients. A single case in this series proved to be a polymorphic copy number variant. This paper describes five of the patients with previously unsuspected diagnoses in detail. We suggest that array CGH is an improved tool ready for routine use in clinical genetics.
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http://dx.doi.org/10.1002/ajmg.a.31417DOI Listing
October 2006

Incontinentia pigmenti in a boy with XXY mosaicism detected by fluorescence in situ hybridization.

J Am Acad Dermatol 2006 Jul;55(1):136-8

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.

We report the case of a male infant with incontinentia pigmenti (MIM 308310) and low-grade XXY mosaicism. Fluorescence in situ hybridization may reveal the underlying genetic alteration in male patients with incontinentia pigmenti and a normal karyotype.
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http://dx.doi.org/10.1016/j.jaad.2005.11.1068DOI Listing
July 2006