A de novo in-frame deletion of CASK gene causes early onset infantile spasms and supratentorial cerebral malformation in a female patient

2018 ◽  
Vol 176 (11) ◽  
pp. 2425-2429 ◽  
Author(s):  
Xiuhua Bozarth ◽  
Kimberly Foss ◽  
Heather C. Mefford
Keyword(s):  
Female Patient ◽  
Early Onset ◽  
De Novo ◽  
Infantile Spasms ◽  
Cerebral Malformation

Early-onset presentation of a new subtype of β-Propeller protein-associated neurodegeneration (BPAN) caused by a de novo WDR45 deletion in a 6 year-old female patient

2020 ◽  
Vol 63 (3) ◽  
pp. 103765 ◽  
Author(s):  
Stephanie Christoforou ◽  
Kyproula Christodoulou ◽  
Violetta Anastasiadou ◽  
Paola Nicolaides
Keyword(s):  
Female Patient ◽  
Early Onset ◽  
De Novo

scholarly journals Pediatric leukemia susceptibility disorders: manifestations and management

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 242-250 ◽  
Author(s):  
Lisa J. McReynolds ◽  
Sharon A. Savage
Keyword(s):  
Early Onset ◽  
Ribosome Biogenesis ◽  
De Novo ◽  
Disease Risk ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Cancer Surveillance ◽  
Therapeutic Interventions ◽  
Pediatric Leukemia ◽  
Inherited Susceptibility

Abstract The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer

2011 ◽  
Vol 10 (2) ◽  
pp. 233-237 ◽  
Author(s):  
Ava Kwong ◽  
Enders K. O. Ng ◽  
Edmund Y. H. Tang ◽  
Chris L. P. Wong ◽  
Fian B. F. Law ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
De Novo ◽  
Brca1 Mutation ◽  
Chinese Woman ◽  
Early Onset Breast Cancer

Infantile Spasms: Current Therapy and Progress

1996 ◽  
Vol 17 (10) ◽  
pp. 356-356
Author(s):  
Steven M. Wolf ◽  
Karen Ballaban-Gil
Keyword(s):  
Inborn Error ◽  
Central Nervous System Infection ◽  
Intrauterine Infection ◽  
Infantile Spasms ◽  
Current Therapy ◽  
Genetic Abnormality ◽  
Cerebral Malformation ◽  
Age Dependent ◽  
Muscle Groups ◽  
Degenerative Disorder

Infantile spasms represent an age-dependent epileptic syndrome that usually begins between 4 and 6 months of life; onset is before the age of 12 months in about 90% of cases. The spasms are characterized by symmetric, bilateral, brief, and sudden contractions of the flexor or extensor muscle groups. The seizures may be resistant to treatment, and the syndrome frequently is associated with mental retardation. In 14% to 38% of cases, infantile spasms are "cryptogenic," without identifiable underlying cause. However, the majority of patients have so-called "symptomatic" infantile spasms, with some identifiable pre-, peri-, or postnatal factor that underlies the syndrome: hypoxemiaischemia, intrauterine infection, a cerebral malformation or degenerative disorder, tuberous sclerosis, a genetic abnormality, an inborn error of metabolism, an intracranial hemorrhage, traumatic delivery, head injury, or a central nervous system infection.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Siddharth K Prakash ◽  
Angela T Yetman ◽  
Hector I Michelena ◽  
Malenka M Bissell ◽  
Yuli Y Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Early Onset ◽  
Rare Variants ◽  
De Novo ◽  
Late Onset ◽  
Copy Number Variants ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

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