Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.
Background/Aim: The aim of this study was to use targeted next-generation sequencing (TNGS) including all known genes associated with 46,XY disorders of sex development (DSD) for a fast molecular genetic diagnosis. Methods: Twenty pediatric patients were recruited, and 56 genes related to 46,XY DSD were sequenced using TNGS. The time elapsed between initial appointment and final diagnosis as well as the mean expenditure was determined. Results: A total of 9 (45%) mutations in 4 different genes were identified. Mutations in the HSD17B3 gene were observed in 6 (30%) patients. A heterozygous mutation in WT1 gene and a hemizygous mutation in SRY gene were detected in patients with gonadal dysgenesis. One patient had a homozygous mutation in LHCGR gene. Prior to the molecular diagnosis, the mean number of clinical visits, time elapsed until diagnosis, and expenditure were 27.4 ± 14.6 visits, 5.9 ± 4.1 years per patient, and USD 2,142 ± 1,038, respectively. With TNGS, time elapsed until diagnosis was significantly reduced (3 days), and expenditure per patient was only one third of the conventional approach (USD 761). Conclusions: TNGS is an efficient, rapid, and cost-effective technique for mutation detection in 46,XY DSD.
Von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by benign or malignant tumors which may involve more than one system. Retinal hemangioblastomas are usually the initial manifestation of VHL disease and can cause vision loss. A 32-year-old man presented to our clinic with vision loss in the left eye for 2 months. He had a history of cerebral hemangioblastoma operation. Family history showed that his mother had unilateral vision loss and died because of renal cell carcinoma. Ophthalmologic examination revealed multiple retinal hemangioblastomas in both eyes. VHL gene sequencing was performed and heterozygous p.R161X mutation was detected. His sister and daughter were also found to have the same variant. A treatment and follow-up plan was initiated for the patient and affected family members. Considering VHL disease in the differential diagnosis of retinal hemangioblastomas has a very important role in the early detection of life-threatening tumors in these patients.
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