Persistent Hyperplastic Primary Vitreous with Microphthalmia and Coloboma in a Patient with Okur-Chung Neurodevelopmental Syndrome

Okur-Chung neurodevelopmental syndrome is a rare autosomal dominant disorder caused by pathogenic variants in <i>CSNK2A1</i>, which encodes the alpha 1 catalytic subunit of casein kinase II. This syndrome is characterized by intellectual disability, developmental delay, and multisystemic abnormalities including those of the brain, extremities, and skin as well as cardiovascular, gastrointestinal, and immune systems. In this study, we describe a 5-year-old boy with a de novo novel nonsense variant in <i>CSNK2A1</i>, NM_001895.3:c.319C>T (p.Arg107*). He showed bilateral persistent hyperplastic primary vitreous with microphthalmia, lens dysplasia, and coloboma. Ocular manifestations are very rare in this syndrome, and this study expands the spectrum of the clinical presentations of this syndrome.

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NR2F1 database: 111 variants and 83 patients support refining the clinical synopsis of Bosch-Boonstra-Schaaf optic atrophy syndrome

10.22541/au.162499324.41147632/v1 ◽

2021 ◽

Author(s):

Benjamin Billiet ◽

Patrizia Amati-Bonneau ◽

Valérie Desquiret-Dumas ◽

Khadidja Guehlouz ◽

Dan Milea ◽

...

Keyword(s):

Intellectual Disability ◽

Optic Atrophy ◽

Autosomal Dominant ◽

Clinical Presentation ◽

Autosomal Dominant Disorder ◽

Feeding Difficulties ◽

Pathogenic Variants ◽

Neurological Features ◽

Clinical Description ◽

Nuclear Receptor Subfamily

Pathogenic variants of the nuclear receptor subfamily 2 group F member 1 gene (NR2F1) are responsible for Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), an autosomal dominant disorder characterized by optic atrophy associated with developmental delay and intellectual disability, but with a clinical presentation which appears to be multifaceted. We created the first public locus-specific database (LSDB) dedicated to NR2F1. All variants and clinical cases reported in the literature, as well as new unpublished cases, were integrated into the database using standard nomenclature to describe both molecular and phenotypic anomalies. We subsequently pursued a comprehensive approach based on computed representation and analysis suggesting a refinement of the BBSOAS clinical description with respect to neurological features and the inclusion of musculoskeletal hypotonia and intestinal signs with feeding difficulties. This database is fully accessible for both clinician and molecular biologists and should prove useful in further refining the clinical synopsis of NR2F1 as new data is recorded.

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A Japanese Patient with Genitopatellar Syndrome Transiently Presenting with Cardiac Intramural Cavity during the Neonatal Period

Case Reports in Genetics ◽

10.1155/2020/1731720 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Kiichi Takahashi ◽

Hiroyuki Adachi ◽

Manatomo Toyono ◽

Masato Ito ◽

Akie Kato ◽

...

Keyword(s):

Autosomal Dominant ◽

De Novo ◽

Heart Defects ◽

Ductus Arteriosus ◽

Renal Cysts ◽

Ventricular Septal Defects ◽

Autosomal Dominant Disorder ◽

Septal Defects ◽

Pathogenic Variants

Genitopatellar syndrome (GPS) is a rare autosomal dominant disorder caused by de novo pathogenic variants in the KAT6B gene. It is characterized by genital abnormalities, patellar hypoplasia/agenesis, flexion contractures of the hips and knees, corpus callosum agenesis with microcephaly, and hydronephrosis and/or multiple renal cysts. More than half of patients with GPS have congenital heart defects, mostly atrial and/or ventricular septal defects, patent foramen ovale, and patent ductus arteriosus. We report a case of a Japanese neonate with a de novo heterozygous c.3769_3772delTCTA pathogenic variant in the KAT6B gene who presented with a cardiac intramural cavity of the ventricular septum at birth. The cavity unexpectedly disappeared at 1 month of age, but trabecular septal thinning and flash remained. The features of the cavity were not consistent with those of congenital ventricular diverticulum or aneurysm, and its identity and prognosis are still unclear. Because patients with GPS may exhibit various forms of cardiac malformation, careful cardiac examination and follow-up are required from birth in cases of suspected GPS.

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A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01033-4 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Giada Moresco ◽

Jole Costanza ◽

Carlo Santaniello ◽

Ornella Rondinone ◽

Federico Grilli ◽

...

Keyword(s):

Intellectual Disability ◽

Clinical Presentation ◽

De Novo ◽

Clinical Signs ◽

Missense Variant ◽

Psychomotor Development ◽

Helicase Domain ◽

Protein Activity ◽

Mrna Metabolism ◽

Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma

Human Genome Variation ◽

10.1038/s41439-020-00124-8 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Saba Ahmad ◽

Luis Manon ◽

Gifty Bhat ◽

Jerry Machado ◽

Alice Zalan ◽

...

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cellular Differentiation ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Disease ◽

Sacrococcygeal Teratoma ◽

Dominant Disease ◽

The Brain

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

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Eye Manifestations of Shprintzen–Goldberg Craniosynostosis Syndrome: A Case Report and Systematic Review

Case Reports in Genetics ◽

10.1155/2020/7353452 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Jamie H. Choi ◽

Rachel Li ◽

Rachel Gannaway ◽

Tahnee N. Causey ◽

Anna Harrison ◽

...

Keyword(s):

Systematic Review ◽

De Novo ◽

Mitral Valve Insufficiency ◽

Ocular Manifestations ◽

Pathogenic Variants ◽

Ophthalmic Manifestations ◽

Valve Insufficiency ◽

Aortic Root Dilatation ◽

History Of ◽

Tissue Abnormalities

Shprintzen–Goldberg craniosynostosis syndrome (SGS) is a rare autosomal dominant condition that was first documented in literature in 1982. The disorder is caused by pathogenic variants in the proto-oncogene SKI gene, a known suppressor of TGF-β activity, located on chromosome 1p36. There is considerable phenotypic overlap with Marfan and Loeys–Dietz syndromes. Common clinical features of SGS include craniosynostosis, marfanoid habitus, hypotonia, dysmorphic facies, cardiovascular anomalies, and other skeletal and connective tissue abnormalities. Ocular manifestations may include hypertelorism, downslanting palpebral fissures, proptosis, myopia, and ectopia lentis. We describe a 25-year-old male with the syndrome. Genetic analysis revealed a novel c.350G>A (p.Arg117His) de novo variant, which was predicted to be pathogenic by the CTGT laboratory. The patient presented with dysmorphic features, marfanoid habitus, severe joint contractures, mitral valve insufficiency, aortic root dilatation, and a history of seizures. His ocular manifestations included hypertelorism, downslanting palpebral fissures, bilateral ptosis, and high myopia. Ophthalmic manifestations are an integral component of the syndrome; however, they have not been well characterized in the literature. From a systematic review of previously published cases to date, we summarize the eye and ocular adnexa manifestations reported.

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Gene discoveries in autism are biased towards comorbidity with intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106476 ◽

2020 ◽

Vol 57 (9) ◽

pp. 647-652

Author(s):

Matthew Jensen ◽

Corrine Smolen ◽

Santhosh Girirajan

Keyword(s):

Intellectual Disability ◽

Genetic Factors ◽

De Novo ◽

High Functioning Autism ◽

Copy Number Variants ◽

Social Responsiveness ◽

High Functioning ◽

Pathogenic Variants ◽

Increased Risk ◽

Normal Cognitive Function

BackgroundAutism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.MethodsWe analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.ResultsIndividuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10−6) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.ConclusionsPathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

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A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715639 ◽

2020 ◽

Author(s):

Ivona Vrkić Boban ◽

Futoshi Sekiguchi ◽

Mirela Lozić ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Chromosomal Abnormalities ◽

Chromosome Translocation ◽

Behavioral Disorder ◽

Behavioral Difficulties ◽

Speech Impairment ◽

Balanced Translocation ◽

Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

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Tuberous Sclerosis and Autism

10.1093/med/9780199744312.003.0009 ◽

2013 ◽

Author(s):

Dan Ehninger ◽

Alcino J. Silva

Keyword(s):

Tuberous Sclerosis ◽

Autosomal Dominant ◽

De Novo ◽

Single Gene ◽

Gene Mutations ◽

Extended Version ◽

Single Gene Disorder ◽

Autosomal Dominant Pattern ◽

Organ Systems ◽

The Brain

Tuberous sclerosis (TSC) is a single-gene disorder caused by heterozygous mutations in either the TSC1 or TSC2 genes (Consortium, 1993; van Slegtenhorst et al., 1997). In 70% of cases, TSC gene mutations arise de novo. The remaining 30% of cases are familial with an autosomal dominant pattern of inheritance. Tuberous sclerosis belongs to the group of phakomatoses (neurocutaneous disorders) and is associated with characteristic manifestations in various organ systems, including the brain, skin, kidney, lung, heart, and liver (Crino, Nathanson, & Henske, 2006; Curatolo, Bombardieri & Jozwiak, 2008). Pathological manifestations in these organ systems often include tumor growths or tissue malformations (hamartomas). While penetrance is high, expressivity of TSC phenotypes is highly variable. The birth incidence of TSC is approximately 1:6,000 (Osborne, Fryer, & Webb, 1991). This chapter is an updated and extended version of a previous article on this topic (Ehninger, de Vries, & Silva, 2009)

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