OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs.
METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics.
RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time.
CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.
Methodology: This was a cross-sectional study. Thirty-four (34) Turner patients were examined for Turner-specific clinical features. The karyotype, clinical features at presentation, age at diagnosis and physiologic features were retrieved from their medical records.
Results: Patients with 45,X presented at a median age of 1 month old with predominantly lymphoedema and webbed neck. Patients with chromosome mosaicism or structural X abnormalities presented at a median age of 11 years old with a broader clinical spectrum, short stature being the most common presenting clinical feature. Cubitus valgus deformity, nail dysplasia and short 4th/5th metacarpals or metatarsals were common clinical features occurring in 85.3%-94.1% of all Turner patients. Almost all patients aged ≥2 years were short irrespective of karyotype.
Conclusion: Although short stature is a universal finding in Turner patients, it is usually unrecognised till late. Unlike the 45,X karyotype, non-classic Turner syndrome has clinical features which may be subtle and difficult to discern. Our findings underscore the importance of proper serial anthropometric measurements in children. Awareness for the wide spectrum of presenting features and careful examination for Turner specific clinical features is crucial in all short girls to prevent a delay in diagnosis.
CASE: We report on a 19-year-old who is phenotypically male, with a 46,XX/46,XY mosaicism karyotype, who presented later in life with cyclical abdominal pain that resembled menstrual cramps and unilateral undescended testes.
SUMMARY AND CONCLUSION: He underwent laparoscopic hysterectomy and right salpingo-oophorectomy, resulting in cessation of his symptoms and improved sperm count.