Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, ...these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish.
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less ...frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and ...previously reported individuals.
Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.
The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.
We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”
The Toroidal Field (TF) coils for the ITER device will represent the largest superconducting magnet system assembled to date, and thus creates several challenges related to the manufacture of these ...magnets. Most notably, the electrical insulation for the TF coils must address four simultaneous constraints: high radiation, large mechanical stresses, high voltage operation, and operation in a vacuum. In addition, these materials must meet all shipping and local environmental regulations for use in large quantities in both Europe and Japan. The TF coil insulation will undergo fast neutron fluences up to 3.2 \times 10^{21}\ \hbox{n/m}^{2} , which is equivalent to 10 MGy, and still be able to withstand the estimated operation in-plane shear stress in the range of 45 MPa. To address this need, CTD has developed and qualified two epoxy/cyanate ester resin systems, CTD-425 and CTD-435. These materials meet the processing requirements, mechanical strength after 30 000 load cycles, and radiation exposure specifications established by ITER IO. Both materials are qualified for use in constructing the ITER TF coils, and are supplied to European and Japanese customers by Lord Corporation. This paper summarizes the performance characterization, qualification tests, and supply chain for these materials.
The ability to interrogate the genome via chromosomal microarray and sequencing-based technologies has accelerated the ability to rapidly and accurately define etiologies as well as new candidate ...genes related to genetic conditions. We describe a male patient with a lethal presentation of a multiple congenital anomaly syndrome that appeared consistent with a ciliopathy phenotype. The patient was found to have a novel maternally inherited 1.9-Mb X chromosome deletion including 4 known genes. Presently, the biological functions of these genes are not well delineated. However, at least one of these genes may be a promising candidate gene for this pattern of anomalies based on the function of related genes and information from publicly available copy number variant databases of control and affected individuals. These genes would bear further scrutiny in larger cohorts of patients with similar phenotypes.
The national importance of telemedicine for safe and effective patient care has been highlighted by the current COVID-19 pandemic. Prior to the 2020 pandemic the Division of Genetics and Metabolism ...piloted a telemedicine program focused on initial and follow-up visits in the patients' home. The goals were to increase access to care, decrease missed work, improve scheduling, and avoid the transport and exposure of medically fragile patients. Visits were conducted by physician medical geneticists, genetic counselors, and biochemical dietitians, together and separately. This allowed the program to develop detailed standard operating procedures. At the onset of the COVID-19 pandemic, this pilot-program was deployed by the full team of 22 providers in one business day. Two physicians remained on-site for patients requiring in-person evaluations. This model optimized patient safety and workforce preservation while providing full access to patients during a pandemic. We provide initial data on visit numbers, types of diagnoses, and no-show rates. Experience in this implementation before and during the pandemic has confirmed the effectiveness and value of telemedicine for a highly complex medical population. This program is a model that can and will be continued well-beyond the current crisis.
Abstract
Background
Male androgenic alopecia is a common cause of hair loss in both men and women. Although genetic and hormonal factors likely play a role, the etiology is mostly unknown. PCOS is a ...highly heritable disease with elevated prevalence of reproductive abnormalities in first-degree relatives (FDRs) of patients with PCOS, which may be due to an underlying genetic defect in steroidogenesis. A recent meta-analysis revealed that male FDRs of patients with PCOS had significantly increased levels of DHEAS compared with controls. We present a young adult male who developed acute hair loss with biochemical evidence of hyperandrogenism.
Clinical Case
A 21-year-old man presented for evaluation of hyperandrogenism after experiencing progressive loss of posterior patch of hair over 3 weeks. He also endorsed acne, intermittent headaches, striae, and difficulty losing weight for the past 2 years. He denied facial rounding, vision changes, and use of glucocorticoids or supplements. Physical examination was notable for height of 67 inches, BMI 30.5 mg/m 2, BP 120/78, recession of the frontotemporal and occipital hairline, sparse posterior scalp hair, bulbous nose, long philtrum, mild facial acne, 2, 3 toe syndactyly, and thin purple striae on bilateral flanks and axillae. Labs revealed elevated DHEAS 1065.7 mcg/dL (ref. 238.4-539.3) and normal 8 AM total testosterone of 382 ng/dL (240-871). Cosyntropin stimulation test revealed baseline cortisol level of 10.6 mcg/dL with ACTH of 22.2 pg/mL (5-46) and 60-minute cortisol level of 24.8 mcg/dL, 17-OH progesterone level 81 ng/dL (18-164), and 17-OH pregnenolone 1040 ng/dL (55-455). Workup for Cushing's revealed multiple normal midnight salivary cortisol levels and mild intermittent elevation of 24-hour urinary free cortisol levels. CT scan of the adrenals was negative for a mass. Exome sequencing revealed a heterozygous de novo pathogenic variant (c.1614_1615delTCinsAT: p. C538X) in the TRPS1 gene (NM_0141112.2). Family history was significant for a 20-year-old sister with PCOS and elevated DHEAS of 443 ug/dL (51-321). Mid-parental height was 69.6 inches.
Conclusion
Trichorhinophalangeal syndrome Type 1 (TRPS1) is a rare genetic disorder characterized by hair, craniofacial, and skeletal abnormalities such as androgenetic alopecia, bulbous nasal tip, and cone-shaped epiphyses. To our knowledge, the hair findings in TRPS are not associated with hyperandrogenism which prompted further investigation. Evaluation for endocrine causes of hyperandrogenism such as Cushing's disease, congenital adrenal hyperplasia, and adrenal tumor were negative. However, our patient's elevated DHEAS is likely due to male PCOS, as previously described in male FDRs of patients with PCOS. Thus, genetic susceptibility to PCOS and rare genetic syndromes should be considered in the differential diagnosis of young men with clinical and biochemical evidence of hyperandrogenism. Reference: Shan D et al. Reproductive Health in First-degree relatives of Patients with Polycystic Ovarian Syndrome: a Review and Meta-analysis. JCEM. 2022 Jan;107(1); 273-295.
Presentation: No date and time listed
Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification ...center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1–8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.
•We describe a new genetic etiology of Catel-Manzke syndrome.•Multisystemic features other than hyperphalangism include spine, heart, renal, and inner ear malformations.•Detection of xanthurenic aciduria on biochemical testing can aid in the differential diagnosis of hyperphalangism.
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less ...frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
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