Publications by authors named "Josue Flores-Daboub"

8 Publications

  • Page 1 of 1

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Am J Med Genet A 2021 06 30;185(6):1649-1665. Epub 2021 Mar 30.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
June 2021

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Parkes Weber syndrome associated with two somatic pathogenic variants in .

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Pathology, University of Utah, Salt Lake City, Utah 84108, USA.

Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in consistent with the c.934_938del, p.(Glu312Argfs*14) and the c.2925del, p.(Asn976Metfs*20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the gene in DNA from a vascular lesion.
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http://dx.doi.org/10.1101/mcs.a005256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476407PMC
August 2020

Detecting mosaic variants in patients with somatic overgrowth syndromes using cell-free circulating DNA and deep sequencing.

J Med Genet 2020 11 28;57(11):794-796. Epub 2020 Jan 28.

Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

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http://dx.doi.org/10.1136/jmedgenet-2019-106732DOI Listing
November 2020

Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.

Am J Hum Genet 2020 01 26;106(1):129-136. Epub 2019 Dec 26.

Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address:

Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042491PMC
January 2020

New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.

BMC Med Genomics 2019 07 9;12(1):105. Epub 2019 Jul 9.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.

Background: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

Methods: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity.

Results: We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation.

Conclusions: Here we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary "benign" versus "pathogenic" scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.
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http://dx.doi.org/10.1186/s12920-019-0555-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617651PMC
July 2019

Non-Immune Hydrops, Hypotonia, Encephalopathy, and Liver Failure with Novel Compound Heterozygous AHCY Mutations.

Neonatology 2018 17;114(4):337-340. Epub 2018 Aug 17.

Division of Pediatric Clinical Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.

A late-preterm infant with a prenatal diagnosis of non-immune hydrops was born with hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days of life due to multisystem organ failure. Rapid whole exome sequencing revealed novel compound heterozygous mutations in the gene encoding S-adenosylhomocysteine hydrolase (AHCY); each novel variant was carried by an asymptomatic parent. Reports of neonates with other AHCY mutations describe a pathology of varying severity. AHCY mutations should be considered when seeking an etiology for neonates with the combination of non-immune hydrops, hypotonia, encephalopathy, and liver failure.
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http://dx.doi.org/10.1159/000489292DOI Listing
September 2019

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Am J Hum Genet 2018 01 21;102(1):27-43. Epub 2017 Dec 21.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777383PMC
January 2018