Publications by authors named "Lorraine Potocki"

76 Publications

Evidence that FGFRL1 contributes to congenital diaphragmatic hernia development in humans.

Am J Med Genet A 2021 03 14;185(3):836-840. Epub 2021 Jan 14.

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

Fibroblast growth factor receptor-like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf-Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf-Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left-sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.
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http://dx.doi.org/10.1002/ajmg.a.62066DOI Listing
March 2021

Short stature and growth hormone deficiency in a subset of patients with Potocki-Lupski syndrome: Expanding the phenotype of PTLS.

Am J Med Genet A 2020 09 13;182(9):2077-2084. Epub 2020 Jul 13.

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

Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well.
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http://dx.doi.org/10.1002/ajmg.a.61741DOI Listing
September 2020

TSC1 Variant Associated With Mild or Absent Clinical Features of Tuberous Sclerosis Complex in a Three-Generation Family.

Pediatr Neurol 2020 09 4;110:89-91. Epub 2020 May 4.

Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.017DOI Listing
September 2020

Management of Sleep Disturbances Associated with Smith-Magenis Syndrome.

CNS Drugs 2020 07;34(7):723-730

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

Smith-Magenis syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 (RAI1) gene that maps on the short arm of chromosome 17p11.2 or a pathogenic mutation of RAI1. Smith-Magenis syndrome affects patients through numerous congenital anomalies, intellectual disabilities, behavioral challenges, and sleep disturbances. The sleep abnormalities associated with Smith-Magenis syndrome can include frequent nocturnal arousals, early morning awakenings, and sleep attacks during the day. The sleep problems associated with Smith-Magenis syndrome are attributed to haploinsufficiency of the RAI1 gene. One consequence of reduced function of RAI1, and characteristic of Smith-Magenis syndrome, is an inversion of melatonin secretion resulting in a diurnal rather than nocturnal pattern. Treatment of sleep problems in people with Smith-Magenis syndrome generally involves a combination of sleep hygiene techniques, supplemental melatonin, and/or other medications, such as melatonin receptor agonists, β-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. Improvement in sleep has been shown to improve behavioral outcomes, which in turn improves the quality of life for both patients and their caregivers.
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http://dx.doi.org/10.1007/s40263-020-00733-5DOI Listing
July 2020

GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment.

Am J Med Genet A 2020 05 17;182(5):1167-1176. Epub 2020 Mar 17.

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

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss-of-function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot-Marie-Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS-associated disease and support that severe early-onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.
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http://dx.doi.org/10.1002/ajmg.a.61544DOI Listing
May 2020

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.

Sci Adv 2020 01 22;6(4):eaax0021. Epub 2020 Jan 22.

Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada.

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.
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http://dx.doi.org/10.1126/sciadv.aax0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976298PMC
January 2020

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability.

J Pediatr Genet 2019 Dec 9;8(4):244-251. Epub 2019 Jul 9.

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

Autosomal recessive variants in the adenosine deaminase, tRNA specific 3 ( ) gene cause a syndromic form of intellectual disability due to a loss of ADAT3 function. This disorder is characterized by developmental delay, intellectual disability, speech delay, abnormal brain structure, strabismus, microcephaly, and failure to thrive. A small subset of individuals with ADAT3 deficiency have other structural birth defects including atrial septal defect, patent ductus arteriosus, hypospadias, cryptorchidism, and micropenis. Here, we report a sibling pair with novel compound heterozygous missense variants that affect a conserved amino acid in the deaminase domain of ADAT3. These siblings have many of the features characteristic of this syndrome, including, intellectual disability, hypotonia, esotropia, failure to thrive, and microcephaly. Both had gastroesophageal reflux disease (GERD), feeding problems, and aspiration requiring thickening of feeds. Although they have no words, their communication abilities progressed rapidly when they began to use augmentative and alternative communication (AAC) devices. One of these siblings was born with an anterior congenital diaphragmatic hernia, which has not been reported previously in association with ADAT3 deficiency. We conclude that individuals with ADAT3 deficiency should be monitored for GERD, feeding problems, and aspiration in infancy. They may also benefit from the use of AAC devices and individualized educational programs that take into account their capacity for nonverbal language development. Additional studies in humans or animal models will be needed to determine if ADAT3 deficiency predisposes to the development of structural birth defects.
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http://dx.doi.org/10.1055/s-0039-1693151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824885PMC
December 2019

Objective measures of sleep disturbances in children with Potocki-Lupski syndrome.

Am J Med Genet A 2019 10 24;179(10):1982-1986. Epub 2019 Jul 24.

Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Potocki-Lupski syndrome (PTLS; MIM 610883) is a neurodevelopmental disorder caused by a microduplication, a 3.7 Mb copy number variant, mapping within chromosome 17p11.2, encompassing the dosage-sensitive RAI1 gene. Whereas RAI1 triplosensitivity causes PTLS, haploinsufficiency of RAI1 due to 17p11.2 microdeletion causes the clinically distinct Smith-Magenis syndrome (SMS; MIM 182290). Most individuals with SMS have an inversion of the melatonin cycle. Subjects with PTLS have mild sleep disturbances such as sleep apnea with no melatonin abnormalities described. Sleep patterns and potential disturbances in subjects with PTLS have not been objectively characterized. We delineated sleep characteristics in 23 subjects with PTLS who underwent a polysomnogram at Texas Children's Hospital. Eleven of these subjects (58%) completed the Child's Sleep Habits Questionnaire (CSHQ). Urinary melatonin was measured in one patient and published previously. While the circadian rhythm of melatonin in PTLS appears not to be disrupted, we identified significant differences in sleep efficiency, percentage of rapid eye movement sleep, oxygen nadir, obstructive apnea hypopnea index, and periodic limb movements between prepubertal subjects with PTLS and previously published normative data. Data from the CSHQ indicate that 64% (7/11) of parents do not identify a sleep disturbance in their children. Our data indicate that younger individuals, <10 years, with PTLS have statistically significant abnormalities in five components of sleep despite lack of recognition of substantial sleep disturbances by parents. Our data support the contention that patients with PTLS should undergo clinical evaluations for sleep disordered breathing and periodic limb movement disorder, both of which are treatable conditions.
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http://dx.doi.org/10.1002/ajmg.a.61307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953247PMC
October 2019

Arnold-Chiari type 1 malformation in Potocki-Lupski syndrome.

Am J Med Genet A 2019 07 8;179(7):1366-1370. Epub 2019 May 8.

Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida.

Potocki-Lupski syndrome (PTLS) is a genetic disorder that results from an interstitial duplication within chromosome 17p11.2. Children with PTLS typically present with infantile hypotonia, failure to thrive, and global developmental delay with or without major organ system involvement. Systematic clinical studies regarding growth, cardiovascular disease, and neurocognitive profiles have been published; however, systematic evaluation of central nervous system structure by magnetic resonance imaging (MRI) of the brain has not been reported. Herein, we describe three patients with PTLS who were found-in the course of routine clinical care-to have a type 1 Arnold-Chiari malformation (CM-1). This finding raises the question of whether the incidence of CM-1 is increased in PTLS, and hence, if an MRI of the brain should be considered in the evaluation of all patients with this chromosomal duplication syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61187DOI Listing
July 2019

Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).

Genet Med 2019 10 3;21(10):2355-2363. Epub 2019 Apr 3.

PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

Purpose: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive.

Methods: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot.

Results: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function.

Conclusions: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.
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http://dx.doi.org/10.1038/s41436-019-0503-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774999PMC
October 2019

Hypertension in Potocki-Shaffer syndrome: A case report.

Eur J Med Genet 2020 Jan 20;63(1):103633. Epub 2019 Feb 20.

Baylor College of Medicine, Department of Pediatrics, USA; Baylor College of Medicine, Renal Section, Department of Pediatrics, and Texas Children's Hospital, USA. Electronic address:

Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI).
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http://dx.doi.org/10.1016/j.ejmg.2019.02.005DOI Listing
January 2020

Current clinical evidence does not support a link between TBL1XR1 and Rett syndrome: Description of one patient with Rett features and a novel mutation in TBL1XR1, and a review of TBL1XR1 phenotypes.

Am J Med Genet A 2018 07 19;176(7):1683-1687. Epub 2018 May 19.

Department of Neurology, Baylor College of Medicine, Houston, Texas.

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http://dx.doi.org/10.1002/ajmg.a.38689DOI Listing
July 2018

Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.

JAMA Pediatr 2017 12 4;171(12):e173438. Epub 2017 Dec 4.

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

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, And Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children's Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes And Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions And Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.
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http://dx.doi.org/10.1001/jamapediatrics.2017.3438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359927PMC
December 2017

Lessons learned from additional research analyses of unsolved clinical exome cases.

Genome Med 2017 03 21;9(1):26. Epub 2017 Mar 21.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

Methods: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

Results: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

Conclusion: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.
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http://dx.doi.org/10.1186/s13073-017-0412-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361813PMC
March 2017

Potocki-Shaffer syndrome in a child without intellectual disability-The role of PHF21A in cognitive function.

Am J Med Genet A 2017 Mar 27;173(3):716-720. Epub 2017 Jan 27.

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

Potocki-Shaffer syndrome is a contiguous gene deletion syndrome involving 11p11.2p12 and characterized by multiple exostoses, biparietal foramina, genitourinary anomalies in males, central nervous system abnormalities, intellectual disability, and craniofacial abnormalities. Current literature implicates haploinsufficiency of three genes (ALX4, EXT2, and PHF21A) in causing some of the cardinal features of PSS. We report a patient with multiple exostoses, biparietal foramina, and history of mild developmental delay. Cognitive and behavioral testing supported formal diagnoses of anxiety, verbal dyspraxia, articulation disorder, and coordination disorder, without intellectual disability. His facial features, though distinctive, were not typical of those observed in PSS. As the chromosomal deletion does not encompass PHF21A, this case lends further support that haploinsufficiency of PHF21A contributes to the intellectual disability and craniofacial abnormalities in PSS and that there are other genes in the region which likely contribute to the behavioral phenotype in this syndrome. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37988DOI Listing
March 2017

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.

Am J Hum Genet 2017 Jan 8;100(1):91-104. Epub 2016 Dec 8.

Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University and McGill University Health Center, Montreal, QC H3A 1A3, Canada. Electronic address:

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223032PMC
January 2017

Severe Pancytopenia in a Premature Infant.

Clin Pediatr (Phila) 2017 07 25;56(8):795-797. Epub 2016 Nov 25.

1 Baylor College of Medicine, Houston, TX, USA.

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http://dx.doi.org/10.1177/0009922816678817DOI Listing
July 2017

Novel EED mutation in patient with Weaver syndrome.

Am J Med Genet A 2017 Feb 21;173(2):541-545. Epub 2016 Nov 21.

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

Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features. Pathogenic variants in EZH2, a histone methyltransferase, have previously been identified as a cause of Weaver syndrome. However, the underlying molecular cause in many patients remains unknown. We report a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic. Reports in the medical literature of EED associated overgrowth prompted re-analysis of the patient's original exome data. The patient was found to have a likely pathogenic variant in EED. These findings support that Weaver syndrome is a disorder with locus heterogeneity and can be due to pathogenic variants in either EZH2 or EED. This case highlights the utility of exome sequencing as a clinical diagnostic tool for novel gene discovery as well as the importance of re-examination of exome data as new information about gene-disease associations becomes available. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38055DOI Listing
February 2017

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

Am J Hum Genet 2016 Oct 15;99(4):831-845. Epub 2016 Sep 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
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http://dx.doi.org/10.1016/j.ajhg.2016.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065660PMC
October 2016

Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith-Magenis and Potocki-Lupski Syndromes.

J Pediatr Genet 2015 Sep 28;4(3):159-67. Epub 2015 Sep 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States; Texas Children's Hospital, Houston, Texas, United States.

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.
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http://dx.doi.org/10.1055/s-0035-1564443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918721PMC
September 2015

Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.

Hum Genet 2016 10 7;135(10):1161-74. Epub 2016 Jul 7.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.
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http://dx.doi.org/10.1007/s00439-016-1703-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021589PMC
October 2016

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Genet Med 2017 01 19;19(1):45-52. Epub 2016 May 19.

Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA.

Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.

Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.

Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.

Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.
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http://dx.doi.org/10.1038/gim.2016.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116288PMC
January 2017

Utility of whole exome sequencing in evaluation of juvenile motor neuron disease.

Muscle Nerve 2016 Apr 22;53(4):648-52. Epub 2016 Feb 22.

Department of Pediatric Neurology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, 77030, USA.

Introduction: This case report focuses on identifying novel mutations in juvenile motor neuron disease and emphasizes the significance of whole exome sequencing (WES).

Methods: We report a 13-year-old Hispanic boy with rapidly progressive weakness, muscle atrophy, tremor, and tongue fasciculation, along with upper motor neuron findings of hyperactive gag reflex, hyperreflexia, and cog-wheel rigidity. Electromyography was suggestive of motor neuron disease. After an extensive evaluation, WES was performed.

Results: WES identified a heterozygous de novo variant of unknown clinical significance (VUS) in the fused-in-sarcoma gene (FUS) [c.1554_1557del]. Although initially reported as a VUS, the clinical data from our patient and data from the medical literature support that the variant is indeed disease-causing.

Conclusions: The genetic etiology of amyotrophic lateral sclerosis (ALS) is heterogeneous and, as clinical sequencing for FUS was not available, WES was the only method by which a diagnosis of juvenile ALS could be made.
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http://dx.doi.org/10.1002/mus.25030DOI Listing
April 2016

Triploidy mosaicism (45,X/68,XX) in an infant presenting with failure to thrive.

Am J Med Genet A 2016 Mar 14;170(3):694-8. Epub 2015 Nov 14.

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

Triploid mosaicism is a rare aneuploidy syndrome characterized by growth retardation, developmental delay, 3-4 syndactyly, microphthalmia, coloboma, cleft lip and/or palate, genitourinary anomalies, and facial or body asymmetry. In the present report, we describe a 3-month-old female presenting with failure to thrive, growth retardation, and developmental delay. A chromosomal microarray demonstrated monosomy X, but her atypical phenotype prompted further evaluation with a chromosome analysis, which demonstrated 45,X/68,XX mixoploidy. To our knowledge, this is the first report of a patient with this chromosome complement. Mosaicism in chromosomal aneuploidies is likely under-recognized and may obscure the clinical diagnosis. At a time when comparative genomic hybridization and genome sequencing are increasingly used as diagnostic tools, this report highlights the clinical utility of chromosome analysis when a molecular diagnosis is not consistent with the observed phenotype.
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http://dx.doi.org/10.1002/ajmg.a.37469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760878PMC
March 2016

Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.

Am J Hum Genet 2015 Nov;97(5):691-707

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.
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http://dx.doi.org/10.1016/j.ajhg.2015.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667131PMC
November 2015

Handing the pen to the patient: reflective writing for children and families affected by genetic conditions.

Am J Med Genet A 2014 Dec 24;164A(12):3021-6. Epub 2014 Sep 24.

Baylor College of Medicine, Houston, Texas.

Genetic diagnoses impact the Quality of Life (QoL) of patients and their families. While some patients and families report a positive impact on QoL, others are affected negatively by a genetic diagnosis. No matter the impact, it is clear that social support is needed for this population. Genetic healthcare providers should be aware of the need for psychosocial support and be equipped to provide or direct patients and families to the appropriate resources. Reflective writing offers a unique opportunity for families and health care providers to engage in self-reflection and expression, activities which have the potential to enhance QoL in a positive manner. The therapeutic potential of writing has been studied in many populations, from caregivers of elderly individuals with dementia, to cancer survivors, to survivors of traumatic experiences. Some of these interventions have shown promise for improving participants' QoL. However, reflective writing has never been studied in patients and families affected by genetic conditions. We propose that reflective writing therapy is a feasible, reproducible, and enjoyable approach to providing psychosocial support for our patients. Get it Write is a reflective writing workshop pilot project for those who have a personal or family history of a genetic diagnosis. Our hypothesis is that reflective writing will help engender acceptance and alleviate feelings of isolation. Get it Write does not focus on the stressful factors in the participants' lives, rather it serves to facilitate interactions with peers facing the same struggles, and with medical students in a non-medical context.
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http://dx.doi.org/10.1002/ajmg.a.36776DOI Listing
December 2014

Inherited dup(17)(p11.2p11.2): expanding the phenotype of the Potocki-Lupski syndrome.

Am J Med Genet A 2014 Feb 5;164A(2):500-4. Epub 2013 Dec 5.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas.

Potocki-Lupski syndrome (PTLS, OMIM: 610883) is a microduplication syndrome characterized by infantile hypotonia, failure to thrive, cardiovascular malformations, developmental delay, intellectual disability, and behavior abnormalities, the latter of which can include autism spectrum disorder. The majority of individuals with PTLS harbor a de novo microduplication of chromosome 17p11.2 reciprocal to the common recurrent 3.6 Mb microdeletion in the Smith-Magenis syndrome critical region. Here, we report on the transmission of the PTLS duplication across two generations in two separate families. Individuals in these families presented initially with developmental delay, behavior problems, and intellectual disability. We provide a detailed review of the clinical and developmental phenotype of inherited PTLS in both families. This represents the second report (second and third families) of PTLS in a parent-child pair and exemplifies the under-diagnosis of this and likely other genetic conditions in adults with intellectual disability and/or psychiatric disorders.
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http://dx.doi.org/10.1002/ajmg.a.36287DOI Listing
February 2014

Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.

Nat Genet 2013 Nov 29;45(11):1405-8. Epub 2013 Sep 29.

1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. [3].

Prader-Willi syndrome (PWS) is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the PWS domain. The first subject was ascertained by whole-genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing the results of exome sequencing of 1,248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of PWS. These findings suggest that MAGEL2 is a new gene causing complex ASD and that MAGEL2 loss of function can contribute to several aspects of the PWS phenotype.
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http://dx.doi.org/10.1038/ng.2776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819162PMC
November 2013