Recent advancements in medical research have been pivotal in deepening our understanding of a variety of health conditions. The utilization of tools such as VarSeq in these studies allows for comprehensive genomic analyses, thereby ensuring more accurate diagnoses and facilitating the development of targeted treatments. This bloghighlights three recent publications that have utilized VarSeq to unravel the mysteries of different medical phenomena: postpartum hyperammonemia due to N-acetyl glutamate synthase (NAGS) deficiency, the role of sex hormones in vascular reactivity in boys with hypospadias, and the link between TINF2 gene and susceptibility to multiple primary melanoma in Danish patients.
Partial N-acetyl glutamate synthase deficiency presenting as postpartum hyperammonemia: Diagnosis and subsequent pregnancy management
N-acetyl glutamate synthase (NAGS) deficiency (OMIM #: 237310) is a rare urea cycle disorder that usually presents early in life with hyperammonemia. NAGS catalyzes the synthesis of N-acetyl glutamate (NAG) which functions as an activator of the carbamoyl phosphate synthetase-1 mediated conversion of ammonia to carbamoyl phosphate. The absence of NAG results in a proximal urea cycle disorder which can result in severe neurologic sequelae secondary to hyperammonemia and even death. Unlike the other urea cycle disorders, a specific pharmacological treatment for NAGS deficiency exists in the form of carglumic acid, an analog of NAG. Here we present a 29-year-old previously healthy female who presented with hyperammonemia and obtundation just after the birth of her first child. Exome sequencing revealed two novel variants in the NAGS gene, and plasma metabolomics revealed extremely low levels of NAG. Carglumic acid treatment led to prompt resolution of her biochemical abnormalities and symptoms. She tolerated two subsequent pregnancies, 2 years and 6 years after her initial presentation, while taking carglumic acid, and breastfed her third child, all without complications in the mother or children. This case report emphasizes the importance of considering urea cycle disorders in previously-healthy adults presenting with neurological symptoms during periods of metabolic stress, including the postpartum period. It also highlights the efficacious and safe use of carglumic acid during pregnancy and while breastfeeding.
Abou Haidar L, Pachnis P, Gotway GK, Ni M, DeBerardinis RJ, McNutt MC. Partial N-acetyl glutamate synthase deficiency presenting as postpartum hyperammonemia: Diagnosis and subsequent pregnancy management. JIMD Reports. 2023;1‐7. doi:10.1002/jmd2.12388
Effects of sex hormones on vascular reactivity in boys with hypospadias
Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear.
We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias.
Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone.
In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17β-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17β-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17β-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04).
In healthy boys, testosterone and 17β-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.
Angela K Lucas-Herald, Augusto C Montezano, Rheure Alves-Lopes, Laura Haddow, Stuart O’Toole, Martyn Flett, Boma Lee, S Basith Amjad, Mairi Steven, Jane McNeilly, Katriona Brooksbank, Rhian M Touyz, S Faisal Ahmed, Effects of sex hormones on vascular reactivity in boys with hypospadias, The Journal of Clinical Endocrinology & Metabolism, 2023;, dgad525, https://doi.org/10.1210/clinem/dgad525
TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma
TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD, POT1, TERF2IP, and TERT. We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers.
Jensen, Marlene & Jelsig, Anne & Gerdes, Anne-Marie & Hölmich, Lisbet & Kainu, Kati & Lorentzen, Henrik & Hansen, Mary & Bak, Mads & Johansson, Peter & Hayward, Nicholas & Hansen, Thomas & Wadt, Karin. (2023). TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma. Human Genetics and Genomics Advances. 4. 100225. 10.1016/j.xhgg.2023.100225.
As science continues to advance, tools like VarSeq play an instrumental role in bolstering research quality and depth. The highlighted studies showcase the importance of genomic analysis in diagnosing and understanding various health conditions. The discoveries in these papers not only pave the way for improved medical interventions but also serve as a testament to the power of collaborative research and state-of-the-art technological tools. It’s an exciting time in the realm of medical research, and the potential for future breakthroughs remains boundless.