Publications by authors named "Marilyn C Jones"

47 Publications

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

Authors:
Sarah E Sheppard Ian M Campbell Margaret H Harr Nina Gold Dong Li Hans T Bjornsson Julie S Cohen Jill A Fahrner Ali Fatemi Jacqueline R Harris Catherine Nowak Cathy A Stevens Katheryn Grand Margaret Au John M Graham Pedro A Sanchez-Lara Miguel Del Campo Marilyn C Jones Omar Abdul-Rahman Fowzan S Alkuraya Jennifer A Bassetti Katherine Bergstrom Elizabeth Bhoj Sarah Dugan Julie D Kaplan Nada Derar Karen W Gripp Natalie Hauser A Micheil Innes Beth Keena Neslida Kodra Rebecca Miller Beverly Nelson Malgorzata J Nowaczyk Zuhair Rahbeeni Shay Ben-Shachar Joseph T Shieh Anne Slavotinek Andrew K Sobering Mary-Alice Abbott Dawn C Allain Louise Amlie-Wolf Ping Yee Billie Au Emma Bedoukian Geoffrey Beek James Barry Janet Berg Jonathan A Bernstein Cheryl Cytrynbaum Brian Hon-Yin Chung Sarah Donoghue Naghmeh Dorrani Alison Eaton Josue A Flores-Daboub Holly Dubbs Carolyn A Felix Chin-To Fong Jasmine Lee Fong Fung Balram Gangaram Amy Goldstein Rotem Greenberg Thoa K Ha Joseph Hersh Kosuke Izumi Staci Kallish Elijah Kravets Pui-Yan Kwok Rebekah K Jobling Amy E Knight Johnson Jessica Kushner Bo Hoon Lee Brooke Levin Kristin Lindstrom Kandamurugu Manickam Rebecca Mardach Elizabeth McCormick D Ross McLeod Frank D Mentch Kelly Minks Colleen Muraresku Stanley F Nelson Patrizia Porazzi Pavel N Pichurin Nina N Powell-Hamilton Zoe Powis Alyssa Ritter Caleb Rogers Luis Rohena Carey Ronspies Audrey Schroeder Zornitza Stark Lois Starr Joan Stoler Pim Suwannarat Milen Velinov Rosanna Weksberg Yael Wilnai Neda Zadeh Dina J Zand Marni J Falk Hakon Hakonarson Elaine H Zackai Fabiola Quintero-Rivera

Am J Med Genet A 2021 Mar 30. Epub 2021 Mar 30.

Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.

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
March 2021

Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

Cold Spring Harb Mol Case Stud 2020 10 7;6(5). Epub 2020 Oct 7.

Rady Children's Institute of Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA.

Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis.
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http://dx.doi.org/10.1101/mcs.a005611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552926PMC
October 2020

Health Supervision for People With Achondroplasia.

Pediatrics 2020 06;145(6)

Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California.

Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential medical complications associated with achondroplasia include lower extremity long bone bowing, middle-ear dysfunction, obstructive sleep apnea, and, more rarely, cervicomedullary compression, hydrocephalus, thoracolumbar kyphosis, and central sleep apnea. This is the second revision to the original 1995 health supervision guidance from the American Academy of Pediatrics for caring for patients with achondroplasia. Although many of the previously published recommendations remain appropriate for contemporary medical care, this document highlights interval advancements in the clinical methods available to monitor for complications associated with achondroplasia. This document is intended to provide guidance for health care providers to help identify individual patients at high risk of developing serious sequelae and to enable intervention before complications develop.
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http://dx.doi.org/10.1542/peds.2020-1010DOI Listing
June 2020

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

Am J Hum Genet 2020 01 26;106(1):121-128. Epub 2019 Dec 26.

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042489PMC
January 2020

Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review.

Clin Dysmorphol 2019 Oct;28(4):175-183

Department of Pediatrics, Division of Genetics and Dysmorphology, UC San Diego/Rady Children's Hospital.

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.
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http://dx.doi.org/10.1097/MCD.0000000000000282DOI Listing
October 2019

Partial Jacobsen syndrome phenotype in a patient with a de novo frameshift mutation in the ETS1 transcription factor.

Cold Spring Harb Mol Case Stud 2019 06 3;5(3). Epub 2019 Jun 3.

Department of Pediatrics, UCSD School of Medicine, La Jolla, California 92093, USA.

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, , has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in , resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1101/mcs.a004010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549550PMC
June 2019

Mutation update for the SATB2 gene.

Hum Mutat 2019 08 18;40(8):1013-1029. Epub 2019 Jun 18.

Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
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http://dx.doi.org/10.1002/humu.23771DOI Listing
August 2019

Whole-exome sequencing reveals novel variant in female fetus with isolated agenesis of the corpus callosum.

Clin Case Rep 2019 Apr 19;7(4):656-660. Epub 2019 Feb 19.

Division of Genetics, Department of Pediatrics University of California San Diego California.

Whole-exome sequencing in a female fetus detected a variant. This X-linked gene was recently associated with intellectual disability and distinct pattern of malformation in females. Isolated agenesis of the corpus callosum has not been reported in association with . Identifying this variant impacted management of the subsequent pregnancy.
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http://dx.doi.org/10.1002/ccr3.2051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452501PMC
April 2019

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

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

King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia. Electronic address:

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

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

NPJ Genom Med 2019 14;4. Epub 2019 Feb 14.

1Illumina, Inc, San Diego, CA 92122 USA.

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% ( = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% ( = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% ( = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
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http://dx.doi.org/10.1038/s41525-018-0076-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375919PMC
February 2019

A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis-lymphedema-telangiectasia syndrome.

Am J Med Genet A 2018 12 14;176(12):2824-2828. Epub 2018 Dec 14.

Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, California.

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare disorder caused by autosomal recessive and autosomal dominant mutations in SOX18. This gene encodes a transcription factor involved in the regulation and development of the human vasculature, lymphatic, and integumentary systems. Individuals with HLTS develop varying degrees of hypotrichosis, lymphedema, and telangiectasias. Other complications, such as renal failure and aortic dilation, have also been observed. Here, we report a neonate with a novel mutation in SOX18 (c.541C>T; p.Gln181stop) presenting with cardinal features of HLTS in addition to unique findings of severe chylothorax and relentless pulmonary hypertension that culminated in death. The purpose of this report is to summarize what is known about this evolving genetic syndrome and to speculate as to how mutations in SOX18 might produce the phenotype.
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http://dx.doi.org/10.1002/ajmg.a.40532DOI Listing
December 2018

Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy.

Am J Hum Genet 2018 10 27;103(4):602-611. Epub 2018 Sep 27.

Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada. Electronic address:

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36 variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.
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http://dx.doi.org/10.1016/j.ajhg.2018.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174287PMC
October 2018

Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.

Eur J Hum Genet 2018 09 14;26(9):1272-1281. Epub 2018 Jun 14.

Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada.

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.
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http://dx.doi.org/10.1038/s41431-018-0187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117294PMC
September 2018

The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.

Cold Spring Harb Mol Case Stud 2018 06 1;4(3). Epub 2018 Jun 1.

Rady Children's Institute for Genomic Medicine, University of California, San Diego, California 92123, USA.

Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in , providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day.
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http://dx.doi.org/10.1101/mcs.a002469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983173PMC
June 2018

A fetal diagnostic center's referral rate for perinatal palliative care.

Ann Palliat Med 2018 Apr 4;7(2):177-185. Epub 2017 May 4.

UCSD Maternal-Fetal Care and Genetics, CA, USA; Department of Radiology, UC San Diego, CA, USA.

Background: Fetal specialists support standardizing the practice of offering women palliative care for life limiting fetal diagnoses. However, there is little data available regarding what fetal specialists do in practice. Since 2003, our center has kept a database of all women referred for fetal complications.

Methods: Retrospective electronic chart review of pregnant women between 2006 and 2012 using UCSD's Fetal Care and Genetics Center referral database. Objectives were to determine: (I) how many high risk pregnancies referred to the University of California San Diego Medical Center (UCSD) over a 6-year period have potentially life limiting fetal diagnoses; (II) pregnancy outcome; and (III) referral rate to perinatal palliative care.

Results: Between July 2006 and July 2012, 1,144 women were referred to UCSD's Fetal Care and Genetics Center, a tertiary care center. Of that cohort, 332 women (29%) were diagnosed prenatally with a potentially life limiting fetal diagnosis. Most women were Hispanic or Latino, married, and had previous children. The median gestation at confirmed diagnosis was 19 weeks. Trisomy 13, Trisomy 18, and anencephaly comprised 21% of cases. The pregnancy outcome was determined in 95% cases: 56% therapeutic abortion, 16% intrauterine fetal demise, and 23% live birth. Only 11% of cases were referred to perinatal palliative care.

Conclusions: The vast majority of women with potentially life limiting fetal diagnoses are not referred to perinatal palliative care. Evaluation of how to integrate palliative care into high-risk obstetrics is needed.
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http://dx.doi.org/10.21037/apm.2017.03.12DOI Listing
April 2018

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

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

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

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

Enlarged Cavum Septi Pellucidi and Vergae in the Fetus: A Cause for Concern.

J Ultrasound Med 2017 Aug 18;36(8):1657-1668. Epub 2017 Apr 18.

Maternal-Fetal Care and Genetics Center, University of California, San Diego, California, USA.

Objectives: To investigate fetal cases identified at our institution to determine whether an enlarged cavum septi pellucidi or cavum vergae is associated with other fetal abnormalities and whether its presence warrants more detailed investigation of the fetus.

Methods: In a retrospective study, 15 high- and low-risk patients undergoing prenatal sonography who had an enlarged cavum septi pellucidi or cavum vergae identified were reviewed. Data were collected for the sonographic study indication, gestation age at diagnosis of a prominent cavum, and associated anomalies. Follow-up outcome data regarding further imaging, karyotype, diagnosis of brain anomaly, and associated congenital abnormalities were obtained.

Results: Fifteen patients met the inclusion criteria. Nine patients were identified as having a prominent cavum septi pellucidi, and 6 were identified as having a prominent cavum vergae. The mean gestational age ± SD was 22.7 ± 5.9 weeks. Eleven patients made it to delivery. Of the 15 patients, 4 were thought to have trisomy 21, and 13 had congenital anomalies. Outcomes included 10 major adverse outcomes, 4 cases with normal development or minor abnormalities, and 1 lost to follow-up. An isolated dilated cavum on prenatal sonography was seen in 5 cases: 1 with lissencephaly on a neonatal examination, 3 premature deliveries (1 demise, 1 hospice, and 1 normal), and 1 unknown.

Conclusions: Our cohort had many associated clinical anomalies: 3 confirmed trisomy 21 and 1 probable trisomy 21, 2 genetic disorders, and 10 major adverse outcomes, 5 of which were grave. Although we studied a small cohort, we conclude that an enlarged cavum septi pellucidi or cavum vergae warrants consideration of genetic counseling, which may include noninvasive prenatal testing (cell-free DNA), amniocentesis with microarray testing, or both.
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http://dx.doi.org/10.7863/ultra.16.06081DOI Listing
August 2017

Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn.

Am J Med Genet A 2017 Jun 6;173(6):1586-1592. Epub 2017 Apr 6.

Department of Pediatrics, University of California San Diego and Rady Children's Hospital - San Diego, San Diego, California.

Curry-Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41-week, 4,165 g, female presented with craniosynostosis, pre-axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations.
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http://dx.doi.org/10.1002/ajmg.a.38232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933242PMC
June 2017

Mutation of WIF1: a potential novel cause of a Nail-Patella-like disorder.

Genet Med 2017 10 6;19(10):1179-1183. Epub 2017 Apr 6.

The Scripps Translational Science Institute, La Jolla, California, USA.

Purpose: Nail-Patella syndrome is a dominantly inherited genetic disorder characterized by abnormalities of the nails, knees, elbows, and pelvis. Nail abnormalities are the most constant feature of Nail-Patella syndrome. Pathogenic mutations in a single gene, LMX1B, a mesenchymal determinant of dorsal-ventral patterning, explain approximately 95% of Nail-Patella syndrome cases. However, 5% of cases remain unexplained.

Methods: Here, we present exome sequencing and analysis of four generations of a family with a dominantly inherited Nail-Patella-like disorder (nail dysplasia with some features of Nail-Patella syndrome) who tested negative for LMX1B mutation.

Results: We identify a loss-of-function mutation in WIF1 (NM_007191 p.W15*), which is involved in mesoderm segmentation, as the suspected cause of the Nail-Patella-like disorder observed in this family.

Conclusions: Mutation of WIF1 is a potential novel cause of a Nail-Patella-like disorder. Testing of additional patients negative for LMX1B mutation is needed to confirm this finding and further clarify the phenotype.Genet Med advance online publication 06 April 2017.
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http://dx.doi.org/10.1038/gim.2017.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629099PMC
October 2017

Evaluation of Ventilation Tube Placement and Long-term Audiologic Outcome in Children With Cleft Palate.

Cleft Palate Craniofac J 2017 11 21;54(6):650-655. Epub 2016 Jul 21.

Objective: The purpose of this study was to assess the effect of ventilation tube (VT) placement on long-term hearing outcomes in children with cleft palate.

Study Design: Case series with chart review.

Setting: Genetic and dysmorphology database at Rady Children's Hospital-San Diego (RCHSD).

Patients: Children with cleft palate diagnosis who underwent surgery at RCHSD between 1995 and 2002.

Main Outcome Measure: The primary outcome studied was hearing acuity at 10 years of age. Independent variables studied included gender, age at palate repair and first VT placement, total number of VTs, number of complications, and presence of tympanic membrane perforation.

Results: An increased number of tubes was associated with a greater incidence of hearing loss at age 10, even after adjusting for total number of otologic complications. The timing of initial tube placement did not have a significant effect on long-term hearing outcome in this study.

Conclusions: While children with worse middle ear disease are more likely to receive more tubes and have long-term conductive hearing loss as a result of ear disease, the results of this study suggest that multiple tube placements may not contribute to improved long-term hearing outcomes. Further research focusing on long-term outcomes is needed to establish patient-centered criteria guiding decision making for ventilation tube placement in children with cleft palate.
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http://dx.doi.org/10.1597/15-349DOI Listing
November 2017

A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.

Am J Hum Genet 2016 06 26;98(6):1256-1265. Epub 2016 May 26.

Clinical Genetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. Electronic address:

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908219PMC
June 2016

Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.

Am J Med Genet A 2016 Apr 5;170A(4):992-8. Epub 2016 Jan 5.

Laboratory for Pediatric Brain Diseases, Howard Hughes Medical Institute, The Rockefeller University, New York City, New York.

Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy.
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http://dx.doi.org/10.1002/ajmg.a.37533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011457PMC
April 2016

Maternal and fetal capillary malformation-arteriovenous malformation (CM-AVM) due to a novel RASA1 mutation presenting with prenatal non-immune hydrops fetalis.

Am J Med Genet A 2015 Oct 11;167A(10):2440-3. Epub 2015 Jun 11.

Division of Genetics, Department of Pediatrics, University of California, San Diego, California.

RASA1 mutations have been shown to cause capillary malformation-arteriovenous malformation (CM-AVM). We describe a patient with CM-AVM and a fetus who presented with non-immune hydrops fetalis during the pregnancy. Sequencing revealed a novel RASA1 mutation in the RASGAP domain that results in a loss of function of p120-RasGap. This report expands our current genetic and clinical understanding of CM-AVM in pregnancy.
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http://dx.doi.org/10.1002/ajmg.a.37203DOI Listing
October 2015

The Society for Craniofacial Genetics and Developmental Biology 37th annual meeting.

Am J Med Genet A 2015 Jul 30;167(7):1455-73. Epub 2015 Mar 30.

Stowers Institute for Medical Research, Kansas City, MO.

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http://dx.doi.org/10.1002/ajmg.a.37012DOI Listing
July 2015

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

J Immunol 2015 Mar 9;194(6):2551-60. Epub 2015 Feb 9.

Department of Medicine, University of California San Diego, La Jolla, CA 92093; Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, CA 92093;

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.
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http://dx.doi.org/10.4049/jimmunol.1401463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355235PMC
March 2015

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility.

Eur J Hum Genet 2015 May 13;23(5):663-71. Epub 2014 Aug 13.

Cytogenetics Laboratory, Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.

Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso- and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso- and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader-Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.
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http://dx.doi.org/10.1038/ejhg.2014.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402629PMC
May 2015

Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy.

Case Rep Genet 2014 3;2014:508231. Epub 2014 Feb 3.

University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA ; Department of Human Genetics, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in the LMNA gene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of the LMNA gene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD) analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3-q22 region flanking the LMNA locus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient.
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http://dx.doi.org/10.1155/2014/508231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930135PMC
March 2014

Impact of Cell-Free Fetal DNA Screening on Patients' Choice of Invasive Procedures after a Positive California Prenatal Screen Result.

J Clin Med 2014 Jul 24;3(3):849-64. Epub 2014 Jul 24.

San Diego, Fetal Care & Genetics San Diego, University of California, CA 92037, USA.

Until recently, maternal serum analyte levels paired with sonographic fetal nuchal translucency measurement was the most accurate prenatal screen available for Trisomies 18 and 21, (91% and 94% detection and false positive rates of 0.31% and 4.5% respectively). Women with positive California Prenatal Screening Program (CPSP) results have the option of diagnostic testing to determine definitively if the fetus has a chromosomal abnormality. Cell-free fetal (cff-) DNA screening for Trisomies 13, 18, and 21 was first offered in 2012, allowing women with positive screens to choose additional screening before diagnostic testing. Cff-DNA sensitivity rates are as high as 99.9% and 99.1%, with false positive rates of 0.4% and 0.1%, for Trisomies 18 and 21, respectively. A retrospective chart review was performed in 2012 on 500 CPSP referrals at the University of California, San Diego Thornton Hospital. Data were collected prior to and after the introduction of cff-DNA. There was a significant increase in the number of participants who chose to pursue additional testing and a decrease in the number of invasive procedures performed after cff-DNA screening was available. We conclude that as fetal aneuploidy screening improves, the number of invasive procedures will continue to decrease.
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http://dx.doi.org/10.3390/jcm3030849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449655PMC
July 2014

Prenatally diagnosed fetal split-hand/foot malformations often accompany a spectrum of anomalies.

J Ultrasound Med 2014 Jan;33(1):167-76

Thornton Hospital, 9300 Campus Point Dr, 7756, La Jolla, CA 92037 USA.

The purpose of this series was to identify cases that appeared on sonography to be split-hand/foot malformations (SHFMs) in fetuses and correlate the sonographic findings, including 2-dimensional (2D) and 3-dimensional (3D) sonography, to outcomes. A retrospective review was conducted of sonographic studies from 2002 to 2012 at 2 fetal care centers. Data were collected with respect to the morphologic characteristics of split-hand/foot abnormalities, the utility of 3D sonography, associated anatomic abnormalities, family histories, gestational ages at diagnosis, fetal outcomes, karyotype, and autopsy results. Ten cases were identified with gestational ages ranging from 15 to 29 weeks. Three-dimensional sonography was helpful in defining anatomy in 7 of 9 cases in which it was performed. Bilateral SHFMs were found in 7 cases (3 cases involving both hands and feet, 2 cases isolated to hands, and 2 cases isolated to feet), whereas 3 cases showed unilateral split-hand malformations. Associated anatomic anomalies were present in 6 cases, and 4 of these had recognized syndromes, including 2 with abnormal karyotypes, specifically, del(22q11) and del(7q31). Two cases occurred in the context of a positive family history of SHFM. Three cases were delivered at term, and 7 cases were electively terminated. In conclusion, SHFMs often occur with a broad range of chromosomal abnormalities, single-gene disorders, and other congenital anomalies. Some apparent SHFMs turn out to be other limb anomalies, such as complex syndactyly. Prenatal screening using 2D sonography can identify SHFMs, and 3D sonography often further clarifies them.
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http://dx.doi.org/10.7863/ultra.33.1.167DOI Listing
January 2014