Mixed Gonadal Dysgenesis with 45,X/46,X,idic(Y)/46,XY Karyotype: A Case Report.

Background: The purpose of the current study was to report a case with 45,X/46,XY/46,X,idic(Yp) mosaicism showing the male phenotype with mixed gonadal dysgenesis. Case Presentation: A 27 year-old individual, phenotypically male, presented with azoospermia and a micropenis. Both testes were not visualized in the scrotal sac. Due to the presence of a small-sized uterus, the individual was referred to the KSHEMA Center for Genetic Services for chromosomal analysis. Karyotyping revealed a mosaic karyotype of 45,X[44]/46,XY[5]/46,X,idic(Yp)[1]. This finding was further confirmed through fluorescent in situ hybridization (FISH) analysis. The individual's mosaic karyotype consisted of three cell lines, with a higher proportion of the 45,X cell line and lower proportions of the idic(Yp) and 46,XY cell lines. It is worth noting that this mosaic condition in postnatal peripheral blood has not been reported in the literature thus far. Conclusion: The case report demonstrated the importance of performing karyotype and FISH analysis in understanding genetic defects including mosaicism and other chromosomal aberrations, which can influence not only growth and puberty but also sexual development and maturation. Hence, performing cytogenetic and molecular cytogenetic analysis will help clinicians to take a further step in understanding and managing the condition.

Detection of Germline Mosaicism for Robertsonian Translocation 14;14: A Case Report.

Background: Chromosomal structural rearrangements can lead to fertility problems and recurrent miscarriages. The intricate interplay of genetics during human development can lead to subtle anomalies that may affect reproduction. Case Presentation: A 33-year-old woman sought fertility treatment after experiencing six miscarriages. Products of conception from the final pregnancy loss had been karyotyped, revealing a Robertsonian translocation (RT), involving chromosome 14. Fertility investigations showed low anti-Mullerian hormone (AMH) levels but otherwise normal female characteristics with normal sperm parameters of her husband were observed and both partners having a normal karyotype. Two embryos were transferred in an IVF cycle but neither resulted in a successful pregnancy. Subsequently, preimplantation genetic testing for aneuploidy (PGT-A) was applied to trophectoderm biopsy specimens from 4 embryos, which revealed abnormalities involving chromosome 14. Sperm aneuploidy testing failed to detect any increase in the incidence of aneuploidy affecting chromosome 14. Further embryos genetic testing indicated that all identified chromosome 14 abnormalities in the embryos had a maternal (oocyte) origin. Conclusion: This case underscores challenges in diagnosing and managing germline mosaicism in fertility. A maternal 14;14 Robertsonian translocation, undetected in the patient's blood but impacting oocytes, likely explains recurrent miscarriage and observed embryo aneuploidies. Genetic mosaicism in reproductive medicine highlights the necessity for advanced testing and personalized treatments. Data integration from various genetic analyses could enhance managing treatment expectations and improving fertility experiences.

BEAM: A combinatorial recombinase toolbox for binary gene expression and mosaic genetic analysis.

We describe a binary expression aleatory mosaic (BEAM) system, which relies on DNA delivery by transfection or viral transduction along with nested recombinase activity to generate two genetically distinct, non-overlapping populations of cells for comparative analysis. Control cells labeled with red fluorescent protein (RFP) can be directly compared with experimental cells manipulated by genetic gain or loss of function and labeled with GFP. Importantly, BEAM incorporates recombinase-dependent signal amplification and delayed reporter expression to enable sharper delineation of control and experimental cells and to improve reliability relative to existing methods. We applied BEAM to a variety of known phenotypes to illustrate its advantages for identifying temporally or spatially aberrant phenotypes, for revealing changes in cell proliferation or death, and for controlling for procedural variability. In addition, we used BEAM to test the cortical protomap hypothesis at the individual radial unit level, revealing that area identity is cell autonomously specified in adjacent radial units.

Mosaic SUFU mutation associated with a mild phenotype of multiple hereditary infundibulocystic basal cell carcinoma syndrome.

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants.

Double somatic mosaicism in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.

Confined placental mosaicism with trisomy 13 complicated by severe preeclampsia: A case report and literature review.

A 31-year-old primiparous woman underwent non-invasive prenatal testing. The result was trisomy 13 (T13) positive. The chromosome 13 t-statistics (Z-score) was significantly high. The result of amniocentesis was normal karyotype (46,XX). Detailed ultrasound showed no fetal structural abnormalities. We suspected T13 confined placental mosaicism (CPM) and observed the course naturally. From the late second trimester, severe fetal growth restriction manifested followed by proteinuria and hypertension, diagnosing her with preeclampsia (PE). At 35 + 5 weeks, emergent cesarean section was required, yielding a 1480 g female infant. We sampled five locations of chorionic villi in the placenta. T13 cells dominated cells with normal karyotypes in all parts and the rate of trisomic cells ranged from 57% to 96%, which were generally high rate. None developed PE in reported T13 CPM cases and this is the first case of PE. The dominancy of T13 cells can be associated with PE development.

Facial Segmental Infantile Haemangioma: A Cutaneous Mosaicism Quandary.

Mosaicism has long been considered the underlying mechanism of segmental infantile hemangiomas (SIH). This was a prospective pilot case-control study conducted with the objective to quantify the percentage overlap of silhouettes of facial SIH with those of Blaschko lines (the most well studied archetypical pattern of mosaicism on face) as compared to other mosaic disorders on face. Lesional silhouettes of 8 patients with SIH (Group A) and 6 patients with other facial dermatosis known to have blaschkoidal distribution (Group B), were overlapped on a standardized template with Blaschkoidal lines on the frontal view of face. The alignment was done via the auto align tool of Photoshop and the percentage of overlap was calculated with an online image comparison software (IMGonline.com.ua). There was a significant difference in mean overlap in Group A (72.92 ± 15.6 %) as compared to Group B (90.1 ± 4.3%; P=0.018). Hence, we concluded that facial SIH do not follow lines of Blaschko.

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Post-zygotic mosaicism of SMARCB1 variants in patients with rhabdoid tumors: a not so rare condition exposing to successive tumors.

BACKGROUND: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by bi-allelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome (RTPS1). With increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel. METHODS: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients. RESULTS: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism. CONCLUSIONS: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.

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Genomic mosaicism arising from mosaic variants is a phenomenon that describes the presence of a cell or cell populations with different genome compositions from the germline cells of an individual. It comprises all types of genetic variants. A large proportion of childhood genetic disorders are defined as being de novo, meaning that the disease-causing mutations are only detected in the proband, not in any of the parents. Population studies show that 80% of the de novo mutations arise from the paternal haplotype, that is, from paternal sperm mosaicism. This review provides a summary of the types and detection strategies of sperm mosaicism. In addition, it provides discussions on how recent studies demonstrated that genomic mosaic mutations in parents, especially those in the paternal sperms, could be inherited by the offspring and cause childhood disorders. According to the previous findings of the author's research team, sperm mosaicism derived from early embryogenesis and primordial germ cell stages can explain 5% to 20% of the de novo mutations related to clinical phenotypes and can serve as an important predictor of both rare and complex disorders. Sperm mosaicism shows great potential for clinical genetic diagnosis and consultations. Based on the published literature, the author suggests that, large-scale screening for de novo sperm mosaic mutations and population-based genetic screening should be conducted in future studies, which will greatly enhance the risk assessment in the offspring and effectively improve the genetic health at the population level. Implementation of direct sperm detection for de novo mutations will significantly increase the efficiency of the stratification of patient cohorts and improve recurrence risk assessment for future births. Future research in the field should be focused on the impact of environmental and lifestyle factors on the health of the offspring through sperms and their modeling of mutation signatures. In addition, targeted in vitro modeling of sperm mutations will also be a promising direction.

Effect of freeze-thawing, cell collection, and laser irradiation cycles on mosaicism occurrence in preimplantation genetic testing for aneuploidy.

OBJECTIVE: In preimplantation genetic testing for aneuploidy, opinions regarding the handling of mosaic embryos vary. In this study, we aimed to investigate the effects of freeze-thawing, the number of cells obtained, and the number of laser irradiation cycles on the degree of embryonic mosaicism. STUDY DESIGN: This study was conducted in three parts. First, we classified specimens into the normal biopsy (control) (119 patients, 304 blastocysts) and thawed-biopsy (TB group) (26 patients, 72 blastocysts)) groups. The control and TB groups were then classified into three categories (euploidy, mosaic and aneuploidy) according to next-generation sequencing (NGS) results, and the number of cells collected and laser irradiation cycles were compared for each category. Subsequently, the effects of differences in the number of cells collected and laser irradiation cycles on NGS results were investigated in the control and TB groups. Finally, data on cell collection and laser irradiation cycles and NGS analysis results for the groups were compared. RESULTS: The TB group had a significantly higher incidence of chromosomal mosaicism than the control group. Neither the number of cells collected nor the laser irradiation cycles affected the percentage of chromosomal mosaicism. However, the freeze-thaw process increased the occurrence of mosaicism. CONCLUSIONS: This study showed that repeated freeze-thaw cycles increase the incidence of mosaicism, but the embryos are not aneuploid and are therefore suitable for transfer.

Body-wide chimerism and mosaicism are predominant causes of naturally occurring ABO discrepancies.

Routine ABO blood group typing of apparently healthy individuals sporadically uncovers unexplained mixed-field reactions. Such blood group discrepancies can either result from a haematopoiesis-confined or body-wide dispersed chimerism or mosaicism. Taking the distinct clinical consequences of these four different possibilities into account, we explored the responsible cause in nine affected individuals. Genotype analyses revealed that more than three-quarters were chimaeras (two same-sex females, four same-sex males, one sex-mismatched male), while two were mosaics. Short tandem repeat analyses of buccal swab, hair root and nail DNA suggested a body-wide involvement in all instances. Moreover, genome-wide array analyses unveiled that in both mosaic cases the causative genetic defect was a unique copy-neutral loss of heterozygosity encompassing the entire long arm of chromosome 9. The practical transfusion- or transplantation-associated consequences of such incidental discoveries are well known and therefore easily manageable. Far less appreciated is the fact that such findings also call attention to potential problems that directly ensue from their specific genetic make-up. In case of chimerism, these are the appearance of seemingly implausible family relationships and pitfalls in forensic testing. In case of mosaicism, they concern with the necessity to delineate innocuous pre-existent or age-related from disease-predisposing and disease-indicating cell clones.

Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.

Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report.

BACKGROUND: Ring chromosome 14 syndrome is a rare disorder primarily marked by early-onset epilepsy, microcephaly, distinctive craniofacial features, hypotonia, intellectual disability, and delay in both development and language acquisition. CASE PRESENTATION: A 21-year-old woman with a history of epileptic seizures since the age of 1.5 years presented with distinctive craniofacial features, including a prominent and narrow forehead, sparse and short eyebrows, palpebral ptosis, horizontal palpebral fissures, a broad nasal bridge, a prominent nasal tip, a flat philtrum, hypertelorism, midfacial hypoplasia, horizontal labial fissures, a thin upper lip, crowded teeth, an ogival palate, retrognathia, and a wide neck. Additional physical abnormalities included kyphosis, lumbar scoliosis, pectus carinatum, cubitus valgus, thenar and hypothenar hypoplasia, bilateral hallux valgus, shortening of the Achilles tendon on the left foot, and hypoplasia of the labia minora. Chromosomal analysis identified a ring 14 chromosome with breakpoints in p11 and q32.33. An aCGH study revealed a ~ 1.7 Mb deletion on chromosome 14qter, encompassing 23 genes. Genomic instability was evidenced by the presence of micronuclei and aneuploidies involving the ring and other chromosomes. CONCLUSION: The clinical features of our patient closely resembled those observed in other individuals with ring chromosome 14 syndrome. The most important point was that we were able to verify an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus.

Fetus Conceived via In Vitro Fertilization With Mosaic Uniparental Isodisomy and Two Balanced Translocations.

We present a case of a fetus acquiring two different balanced translocations from each parent and subsequent uniparental isodisomy from postzygotic loss of a paternal chromosome. Balanced chromosomal translocations occur in 0.14% of the population and increase the risk of other genetic abnormalities, such as uniparental disomy (UPD) and mosaicism. Preimplantation genetic testing (PGT) can identify some genetic abnormalities. Translocations t(6;21) and t(5;15) have been reported individually but never together in a viable fetus. A non-consanguineous couple who were known carriers of two different balanced translocations conceived via classic in vitro fertilization (IVF). They had a normal PGT completed. Chorionic villus sampling (CVS) revealed that the fetus had received t(6;21) from the mother and t(5;15) from the father. The probability of the fetus acquiring both translocations was 2.8%. CVS also revealed UPD of chromosome 14. Amniocentesis was performed, which was consistent with the CVS in detecting the balanced translocations but provided more information about the UPD, determining that it was a mosaic maternal uniparental isodisomy of chromosome 14 (UPD(14)mat). The couple underwent genetic counseling to discuss the above findings and ultimately decided on dilation and evacuation at 17 weeks of gestation. The likelihood of conception of this fetus and survival past the first trimester is extremely rare. These specific chromosomal translocations and (UPD(14)mat) have never been reported before. This case emphasizes the concomitant nature of imprinted genes, resulting in multiple genetically unique alterations. This report also highlights the limitations of PGT, CVS, and amniocentesis in being reproducibly consistent, which is important to discuss prior to IVF conception.

Unusual sex chromosomal DSD in a domestic Shorthair cat with a 37,X/38,XY mosaic karyotype.

BACKGROUND: Sex chromosome abnormalities associated with disorders of sexual development (DSD) are rarely described in cats, mainly due to the lack of chromossome studies that precisely reveal the condition. Genetic approaches are therefore required in order to detect sex chromossomes abnormalities as variations in the number and structure of chromosomes, or the presence of a second cell line as mosaicim or chimerism. CASE PRESENTATION: A male Shorthair cryptorchid cat was presented with clinical signs of anorexia, tenesmus and hyperthermia. Ultrasonography revealed a fluid-filled structure, with approximately 1 cm in diameter, adjacent to the descending colon. Computed tomography evidenced a tubular structure, ventral to the descending colon and caudal to the bladder, which extended cranially, through two branches. Histopathological evaluation confirmed the presence of two atrophic uterine horns and one hypoplastic testicle with epididymis at the end of one of the uterine horns. The end of the other uterine horn was attached to a structure composed by a mass of adipocytes. Cytogenetic analysis revealed a mosaic 37,X/38,XY karyotype. The two cell lines were found in 15% and 85% of the lymphocytes, respectively. Genetic analysis confirmed the presence of SRY and ZFY genes in blood and hair bulbs, and revealed a marked reduction in SRY expression in the testicle. Additionally, this case presented exceptionally rare features, such as a Leydig' cell tumour and a chronic endometritis in both uterine horns. CONCLUSIONS: Complete imaging workup, cytogenetic analysis and SRY gene expression should be systematically realized, in order to properly classify disorders of sexual development (DSD) in cats.

Mosaic distal 9p deletion or 46,XY,del(9)(p23)/46,XY at amniocentesis in a pregnancy associated with perinatal progressive decrease of the aneuploid cell line and a favorable fetal outcome.

OBJECTIVE: We present mosaic distal 9p deletion at prenatal diagnosis in a pregnancy associated with a favorable fetal outcome. CASE REPORT: A 34-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY, del(9)(p23)[8]/46,XY[17]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed 43% mosaicism for the 9p24.3p23 deletion. Prenatal ultrasound suspected hypospadias and echogenic bowel. At 23 weeks of gestation, she was referred for genetic counseling, and repeat amniocentesis revealed a karyotype of 46,XY,del(9)(p23)[10]/46,XY[10]. The parental karyotypes were normal. Molecular genetic analysis on uncultured amniocytes revealed no uniparental disomy (UPD) 9 by quantitative fluorescence polymerase chain reaction (QF-PCR) and arr 9p24.3p23 × 1.55 (40%-50% mosaicism) by aCGH. At 27 weeks of gestation, she underwent the third amniocentesis which revealed a karyotype of 46,XY,del(9)(p23)[6]/46,XY[14]. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed the result of arr 9p24.3p23 (35% mosaicism). Prenatal ultrasound was normal. She was advised to continue the pregnancy, and a 3020-g phenotypically normal male baby was delivered at 41 weeks of gestation. At birth, the karyotypes of cord blood, umbilical cord and placenta were 46,XY,del(9)(p23)[7]/46,XY[37], 46,XY,del(9)(p23)[17]/46,XY[23] and 46,XY in 40/40 cells, respectively. When follow-up at age three months, the neonate was normal in phenotype and development. The peripheral blood had a karyotype of 46,XY,del(9)(p23)[3]/46,XY[37], and interphase fluorescence in situ hybridization (FISH) analysis on buccal mucosal cells showed 13% (13/102 cells) mosaicism for the distal 9p deletion. CONCLUSION: Mosaic distal 9p deletion with a normal cell line at prenatal diagnosis can be associated with a favorable fetal outcome and perinatal progressive decrease of the aneuploid cell line.

Prevalence, diagnostic features, and medical outcomes of females with Turner syndrome with a trisomy X cell line (45,X/47,XXX): Results from the InsighTS Registry.

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly more likely to have structural renal anomalies (18% vs. 3%; p = 0.03). They were twice as likely to have congenital heart disease (32% vs. 15%, p = 0.08) and less likely to experience spontaneous menarche (46% vs. 75% of those over age 10, p = 0.06), although not statistically significant. Congenital anomalies, hypertension, and hearing loss were primarily attributable to a higher proportion of 45,X cells, while preserved ovarian function was most associated with a higher proportion of 46,XX cells. In this large TS cohort, 45,X/47,XXX was more common than previously reported, individuals were phenotypically less affected than those with 45,X, but did have trends for several more TS-related diagnoses than individuals with 45,X/46,XX.