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. 2025 Dec 28;14(1):e70171. doi: 10.1002/mgg3.70171

Genotype–Phenotype Correlations in Klinefelter and Turner Syndrome: A Decade of Sex Chromosome Aneuploidy Data From a Single Academic Medical Center

Stephanie A Hart 1,✉, Joel A Morales‐Rosado 1, Xinxiu Xu 1, Ashwini K Yenamandra 1
PMCID: PMC12745169  PMID: 41457053

ABSTRACT

Background

Klinefelter Syndrome (KS) and Turner Syndrome (TS) are the two most common sex chromosome aneuploidies (SCAs). This study aims to investigate genotype–phenotype correlations of SCAs including classic, rare variants, and mosaic cases of KS and TS.

Methods

To understand the relationship between genotype and phenotype (i.e., clinical findings) in SCAs, retrospective cytogenetic and clinical data was collected for KS (n = 57) and TS (n = 92) cases from 2013 to 2022. The cohorts of KS and TS were divided into three subcategories (classic, mosaic, variant/other) based on the genotype.

Results

The other supernumerary SCA (sSCA) group within the KS cohort had a significantly higher rate of developmental delay when compared to other KS groups. Although tall stature, pubertal delay, and congenital heart defects were described in the KS classic and other sSCA cohorts, these phenotypes were not seen in KS mosaics. Within the TS variant cohort, phenotype severity (i.e., number of accumulated pathologic clinical findings) was related to the complexity of the structural abnormality of X chromosomes.

Conclusion

Our study highlights that the SCA genotype (classic, mosaic, variant/other) modulates expression of the phenotype. Analysis of larger datasets may provide a deeper understanding leading to enhanced care management and improved patient outcomes.

Keywords: genotype–phenotype data correlations in Turner and Klinefelter syndromes, Klinefelter Syndrome, sex chromosome aneuploidy, Turner Syndrome

To understand the relationship between genotype and phenotype in sex chromosome aneuploidies, retrospective cytogenetic and clinical data was collected for Klinefelter Syndrome (n = 57) and Turner Syndrome (n = 92) cases from a single academic medical center from 2013 to 2022. The cohorts were divided into subcategories based on the genotype.

graphic file with name MGG3-14-e70171-g001.jpg

1. Introduction

Sex chromosome aneuploidies (SCAs) are genetic conditions in which individuals have a loss or gain of X and/or Y chromosomes. The most common SCAs in males and females are Klinefelter Syndrome (KS) and Turner Syndrome (TS), respectively.

1.1. Klinefelter Syndrome (KS)

KS is estimated to occur between 1 in 500 and 1 in 1000 live male births and is characterized by the presence of one or more extra X chromosomes (Bojesen et al. 2003; Völkl et al. 2006). The extra X chromosome observed in KS is primarily caused by nondisjunction of either paternal or maternal meiosis in equal proportions (Thomas and Hassold 2003). About 80% of the KS cases demonstrate a 47,XXY karyotype while the remaining 20% include structural variants [i.e., 47,X,i(Xq),Y; 47,XY,der(X); 47,XX,der(Y)], mosaic cases, and other supernumerary SCAs (i.e., 48,XXXY; 48,XXYY; 49,XXXXY; 49,XXXYY) (Bojesen et al. 2003; Visootsak and Graham 2006; Frühmesser and Kotzot 2011; Kanno et al. 2024; Lanfranco et al. 2004; Spaziani et al. 2024).

KS individuals exhibit variable phenotypes including increased height, eunuchoid proportions, hypergonadotropic hypogonadism, azoospermia, small testes, small penis, sparse facial and pubic hair, gynecomastia, behavior and attention disorders, speech and language delays, learning disorders, and autism spectrum disorder (Völkl et al. 2006; Guess et al. 2024; Smyth and Bremner 1998; Abramsky and Chapple 1997; Kleinfelter et al. 1942; Bonomi et al. 2017; Bruining et al. 2009; Groth et al. 2013; Bishop et al. 2011). While patients with mosaicism tend to demonstrate less pronounced phenotypes, patients with other supernumerary SCAs tend to display more severe phenotypes (i.e., an increased number of accumulated pathologic clinical findings) as compared to the classic 47,XXY phenotype (Visootsak and Graham 2006; Frühmesser and Kotzot 2011; Spaziani et al. 2024; Guess et al. 2024; Samplaski et al. 2014; Tartaglia et al. 2011). In addition, KS individuals are at increased risk for developing mediastinal germ cell tumors, diabetes, osteoporosis, mitral valve prolapse, autoimmune diseases, metabolic syndrome, cardiovascular disease, respiratory disease, gastrointestinal disease, obesity, hypothyroidism, neurologic disorders, peripheral vascular disease, breast cancer, psychiatric disturbances, and fractures (Völkl et al. 2006; Guess et al. 2024; Groth et al. 2013; Swerdlow et al. 2001, 2005; Bojesen, Kristensen, et al. 2006; Bojesen, Juul, et al. 2006).

1.2. Turner Syndrome (TS)

TS occurs in approximately 25–50 per 100,000 live female births and is characterized by the complete or partial loss of an X chromosome (Gravholt et al. 2017, 2024; Sybert 2002; Morgan 2007; Homer et al. 2010; Pinsker 2012). About 50% of cases have a classic 45,X karyotype while the remaining 50% demonstrate mosaicism or structural X chromosome abnormalities including deletions of either Xp or Xq [i.e., del(Xp); del(Xq)], rings, unbalanced X‐autosome translocations, and isochromosomes (Gravholt et al. 2017, 2024; Sybert 2002; Morgan 2007; Homer et al. 2010; Pinsker 2012; Ogata et al. 2001; Mercer et al. 2013; Li et al. 2017).

The most common phenotypic features seen in patients with TS include short stature, failure to thrive, lymphedema, dysmorphic features, congenital defects, eye findings (refractive errors, strabismus, amblyopia), learning and attention disorders, psychological conditions, and behavioral problems. Dysmorphic features include craniofacial anomalies (micrognathia, high‐arched palate, deformity of external ears, low posterior hairline), neck findings (broad/short neck, pterygium colli), broad chest with widely spaced nipples, and skeletal findings (cubitus valgus, short fourth metacarpal, developmental dysplasia of the hip, Madelung deformity, genu valgum). Congenital heart defects (bicuspid aortic valve, coarctation of the aorta, partial anomalous pulmonary venous return, septal defect) and genitourinary anomalies (horseshoe kidney, duplex collecting systems, abnormal positioning, renal aplasia) are also common (Gravholt et al. 2017, 2024; Morgan 2007; Pinsker 2012; Moshirfar et al. 2022; Guzewicz et al. 2021). TS individuals are also at risk of developing autoimmune conditions (type 1 diabetes, Hashimoto thyroiditis, Celiac disease, vitiligo, alopecia), hypertension, dyslipidemia, obesity, type 2 diabetes, liver disease, ovarian failure, recurrent otitis media with associated hearing loss, vitamin D deficiency, and scoliosis (Gravholt et al. 2017, 2024; Guzewicz et al. 2021; Tarantino et al. 2025). These phenotypic features have been described in patients with as low as 6% mosaicism (Homer et al. 2010).

Our study aims to investigate the relationship between genotype and phenotype of cohorts of KS and TS using the data collected from a single tertiary medical center over a 10‐year period.

The study will focus on understanding how specific karyotype variants in KS and TS relate to the observable symptoms and progression of these conditions.

2. Materials and Methods

2.1. Ethical Compliance

The study was conducted as a retrospective review of cytogenetic data and qualified for exemption per §46.104(d)(4) by the International Review Board (IRB) (Protocol #240131).

2.2. Data Collection

The cytogenetics archives at our institution were retrospectively reviewed from January 1, 2013 to December 31, 2022 for individuals that were referred for cytogenetic testing by at least one of the following testing methodologies: karyotype, fluorescence in situ hybridization (FISH), or chromosomal microarray analysis (CMA). Demographic, cytogenetic, phenotypic, and interventional data was collected for all cases of KS and TS.

2.3. Cytogenetic Analyses

Cytogenetic analysis was performed on Giemsa‐banded metaphase cells from 24‐h peripheral blood, and results were reported per ISCN 2020 standards. Chromosome analysis was performed by analyzing 20 metaphase cells unless mosaicism was suspected. When mosaicism was suspected in TS, a minimum of 30 metaphase cells was counted, unless the mosaicism was documented within the first 20 cells (Wolff et al. 2010).

FISH analysis was conducted on interphase nuclei from peripheral blood cultures using sex chromosome probes: DXZ1, DYZ3, SRY and control probes D18Z1(OGT's CytoCell, USA).

Genomic DNA was analyzed using the Cytoscan High Density SNP array (Thermo Fisher Scientific, USA) to detect copy number variants (CNVs), deletions, duplications, unbalanced translocations, and copy‐neutral loss of heterozygosity (cnLOH). Results were assessed using laboratory‐defined thresholds.

2.4. Statistical Analysis

KS Cohort: A total of 57 cases of KS were classified into four categories based on the karyotype:

  • –

    KS Classic (KSC): 47,XXY (n = 43);

  • –

    KS mosaic (KSM): 47,XXY/46XY (n = 5);

  • –

    Other supernumerary SCA (Other sSCA) (n = 6): 48,XXXY (n = 3); 48,XXYY (n = 2); 49,XXXY (n = 1);

  • –

    Other mosaic sSCA (n = 3): 47,XXY/48,XXXY/49,XXXXY/46,XY (n = 1); 47,XXY/46,XX (n = 1); and 47,XY + r(X)/46,XY (n = 1)

The KSC group was further subdivided by age at testing into KSC‐neonate (< 0.1 years, n = 6), KSC‐infant/child (0.1–12 years, n = 17), and KSC‐adolescent/adult (> 12 years, n = 20) subgroups.

TS Cohort: The 92 cases of TS included in the study were divided into the following categories:

  • –

    TS Classic (TSC): 45,X (n = 33)

  • –
    TS Variants (TSV) (n = 11): The TSV group was further subdivided based on structural and numerical alterations:
    • ○
      Partial deletion of X chromosome [del(X)] (n = 4) (Figure S1);
    • ○
      Unbalanced X‐autosome translocations [der(X)] (n = 3) (Figure S2);
    • ○
      Isochromosome X [i(X)] with unstable X chromosome due to isodicentric chromosome or presence of 2 GIST genes (n = 3) (Figure S3).
  • –
    TS Mosaic (TSM) (n = 48): The TSM group was further subdivided into TS standard mosaics (TSSM) and six groups of complex mosaics (CM 1–6). CM1‐6 subgroups each showed mosaic TS plus added aberrations in the second non‐TS cell line:
    • ○
      TSSM [45,X/46,XX] (n = 12);
    • ○
      CM1 [45,X/r(X)] (n = 9);
    • ○
      CM2 [45,X/XY] (n = 10) (Figure S4);
    • ○
      CM3 [45,X/del(X)] (n = 6) (Figure S5);
    • ○
      CM4 [45,X/i(X)] (n = 6) (Figure S6);
    • ○
      CM5 [45,X/XXX] (n = 3);
    • ○
      CM6 [45,X/XXX/XX] (n = 2).

The CM2 subgroup also included cases of TS with mosaic 45,X with 46,XY and 47,XYY (n = 1); Yp11.31q11.23 (n = 1); and isodicentric Y chromosome (n = 3).

The TSC cohort was further divided by age at testing into TSC‐pre‐puberty (< 8 years, n = 21) and TSC‐post‐puberty (> 8 years, n = 12) subgroups.

Statistical analyses for variables across diagnostic categories were performed using nonparametric methods due to the skewed distribution of the data. A Kruskal–Wallis rank‐sum test was applied to assess overall differences with pairwise group differences, assessed by post hoc Dunn's multiple comparisons tests with Benjamini–Hochberg false discovery rate (FDR) correction for multiple testing. For each phenotype, referral reason, or clinical intervention differences across subgroups were assessed using the Freeman–Halton extension of Fisher's exact test with FDR correction. All analyses were performed in R (version 4.5.1; R Foundation for Statistical Computing) with R Studio (2025.05.1) using rstatix, dplyr, tidyr, purrr, ggplot2, stringr, logistf, and ggsignif packages. A p value ≤ 0.5 was considered statistically significant. Ideogram representations of chromosomal deletions and rearrangements were generated and modified from CyDAS online web resource (Hiller et al. 2004; Hiller et al. 2005).

3. Results

3.1. KS Cohort

All patients in the KS cohort were documented as males at birth. The KSC‐neonates were referred primarily due to abnormal prenatal testing (67%) and congenital malformations (33%). The most common reasons for referral in the KSC‐infant/child cohort were abnormal prenatal testing (47%) and developmental delay (29%). Meanwhile, hypogonadism (55%) was the main referral reason for testing in adolescents/adults. Thus, abnormal prenatal testing was a significantly more common referral reason in KSC‐neonate and KSC‐infant/child subgroups compared to both KSC‐adolescent/adult and KSM cohorts (p = 0.008).

The KSM cohort had testing for developmental delay (40%), hypogonadism (20%), abnormal prenatal testing (20%), and incidental findings on other testing (20%). Within the Other sSCA cohort, cases were referred for abnormal prenatal testing (33%), developmental delay (33%), and confirmation of results from an outside institution (33%). The Other mosaic sSCA cohort were tested for hypogonadism (33%), to confirm results from an outside institution (33%), and congenital malformations (33%). No statistical significance was seen across these groups when comparing reasons for referrals (Figure 1A, Table S1).

FIGURE 1.

FIGURE 1

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Klinefelter syndrome (KS) Cohort Demographic and Clinical Features. The KS cohort was divided into the following groups: KS classic (KSC) subgroups [neonate, infant/child, adolescent/adult], KS mosaic (KSM), Other supernumerary SCA (Other sSCA), and Other mosaic sSCA. (A) Reason for referral and clinical interventions; (B) Age at testing; (C) Follow‐up time. The global Kruskal–Wallis p value is shown in the upper right corner of each plot. Asterisks in the plots denote statistically significant pairwise comparisons (*p < 0.05; **p < 0.01; ***p < 0.001). Abbreviations: OSH, outside hospital.

For interventions, testosterone therapy was administered to the majority of the KSC‐adolescent/adult (75%) and the Other sSCA (67%) cohorts and only a subset of the KSM (40%), Other mosaic sSCA (33%), and KSC‐infant/child (12%) cohorts. Surgical intervention was less common, observed in 17% (n = 1) of the KSC‐neonate cohort and 24% (n = 4) of the KSC‐infant/child cohort, primarily for cardiac and vascular repairs. Overall, there were no statistically significant differences in therapeutic interventions across the groups (Figure 1A, Table S1).

The KSM cohort had a median age at testing of 8.8 years (range: 0.1–46.7). To better capture age‐related correlations, the KSC cohort was divided into three subgroups based on statistically distinct age distributions: 0 years (range: 0–0.06) for the KSC‐neonate group, 1.4 years (range: 0.1–11.5) for the KSC‐infant/child group, and 17.1 years (range: 12.8–57.0) for the KSC‐adolescent/adult group. The Other sSCA cohort underwent testing primarily in childhood (median: 1.2 years, range: 0–13.1), at ages comparable to those in the KSC‐infant/child subgroup (Figure 1B).

The median follow‐up duration was similar across the KSC age subgroups and other SCA cohorts: 5.1 years (range: 0–7.6) for KSC‐neonate, 3.5 years (range: 0–8.6) for KSC‐infant/child, 5.2 years (range: 0–10.3) for KSC‐adolescent/adult, 1.9 years (range: 0–9.7) for KSM, and 4.9 years (range: 2.7–8.1) for Other sSCA. The follow‐up duration in the KSM and Other SCA cohorts was marginally lower, though this difference did not reach statistical significance (p = 0.605) (Figure 1C). There was no statistically significant difference in the number of phenotypes per individual across the KS cohort (p = 0.163) (Figure 1D).

The most common reported phenotypic features within the KSC‐neonate cohort included musculoskeletal findings (50%), congenital heart defects (50%), developmental delay (33%), craniofacial anomalies (33%), and neurology finding (33%). The KSC‐infant/child cohort commonly demonstrated musculoskeletal findings (53%), developmental delay (41%), eye findings (35%), short stature (29%), learning disorders (29%), congenital heart defects (24%), and cognitive problems (24%). Phenotypic features within the KSC‐adolescent/adult cohort included hypogonadism (100%), small testicles/micropenis (85%), sparse body hair (50%), pubertal delay (45%), tall stature (40%), gynecomastia (40%), obesity (25%), and hyperlipidemia (25%). Across the KSC subgroups, frequent musculoskeletal findings included hand/foot congenital anomalies (i.e., pes planus, clinodactyly), hypotonia, and genu valgum. Myopia and strabismus were the most common eye findings. Recurrent craniofacial anomalies reported included low set ears, micrognathia, microcephaly, and frontal flattening. Cognitive problems were classified as attention deficit disorder. The most common congenital heart defects described were septal defects and patent ductus arteriosus (Figure 2, Table S1).

FIGURE 2.

FIGURE 2

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Klinefelter syndrome (KS) Cohort Phenotype Frequencies. The KS cohort was divided into the following groups: KS classic (KSC) subgroups [neonate, infant/child, adolescent/adult], KS mosaic (KSM), Other supernumerary SCA (Other sSCA), and Other mosaic sSCA. Abbreviations: GU, genitourinary; MSK, musculoskeletal.

Per individual, the KSM cohort demonstrated a median of 6 (range: 0–7) phenotype findings (Figure 1D). However, the KSM cohort demonstrated reduced phenotypic diversity, with fewer distinct types of reported features (n = 16) compared to the KSC‐adult/adolescent cohort (n = 27). Specifically, although reported in the KSC‐adult/adolescent cohort, craniofacial anomalies, neurology findings, sparse body hair, tall stature, pubertal delay, recurrent ear infections, congenital genitourinary anomalies, obesity, hyperlipidemia, hypertension, chest anomalies, and autoimmune diseases were not documented in the KSM cohort. Less than half (40%) of the KSM cohort showed developmental delay, musculoskeletal findings, testicular hypogonadism, learning disorder, cognitive problems, infertility (Figure 2, Table S1).

The Other SCA cohort reported a higher median of 5.5 (range: 0–9) phenotype findings per individual as compared to the KCS‐infant/child cohort median of 4 (range: 1–11) phenotypes per individual (Figure 1D). However, the Other sSCA cohort reported fewer types of phenotypic findings (n = 16) compared to the KSC‐infant/child cohort (n = 26) (Figure 2). The Other sSCA cohort showed a statistically significant frequency of developmental delay (83%) compared to the adolescent KS group (p < 0.05). In addition, the most frequent phenotypes displayed in the Other sSCA cohort included musculoskeletal findings (67%), eye findings (50%), craniofacial anomalies (50%), short stature (50%), learning disorder (33%), autism spectrum disorder (33%), and neurology findings (33%). Common musculoskeletal findings in the Other sSCA cohort were clinodactyly and joint hypermobility. Most frequent eye and facial findings were amblyopia and hypertelorism, respectively. Unlike the KSC‐infant/child cohort, the Other sSCA cohort was not reported to have cognitive problems, recurrent ear infections, hearing loss, congenital genitourinary anomalies, obesity, hyperlipidemia, hypertension, chest abnormalities, autoimmune disease, vitamin D deficiency, or neck abnormalities (Figure 2, Table S1).

3.2. TS Cohort

Of the 92 cases of TS, 94.6% of the cohort was documented as female at birth. A total of five of ten individuals (50%) within the CM2 [45,X/XY] cohort were recorded as male at birth. The remaining 50% were noted as female at birth possibly due to absence of the SRY gene and/or presence of an isodicentric Y chromosome.

The most common reasons for referrals for the TSC‐pre‐puberty subgroup were abnormal prenatal testing (62%), short stature (14%), and confirmation of results from an outside institution (14%). The TSC‐post‐puberty subgroup were tested for short stature (75%) and to confirm results from an outside institution (25%). The TSV del(X) cohort was referred for confirmation of results from an outside institution (50%) and infertility/ovarian failure (50%). The TSV i(X) cohort was referred for short stature (25%), prior abnormal prenatal testing (25%), confirmation of results from an outside institution (25%), and absent menstruation (25%). The TSV der(X) cohort underwent testing for short stature (67%) and for confirmation of results from an outside institution (33%). Across the TSM subgroups, common referral reasons included short stature, prior abnormal prenatal testing, and confirmation of results from an outside institution (Figure 3A, Table S2).

FIGURE 3.

FIGURE 3

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Turner syndrome (TS) Cohort Demographic, Clinical, and Phenotypic Features. The TS cohort was divided into the following groups: TS classic (TSC) subgroups [pre‐puberty, post‐puberty], TS variant (TSV) subgroups [del(X), der(X), i(X)], and TS mosaic (TSM) subgroups (TSSM, CM1, CM2, CM3, CM4, CM5). (A) Reason for referral and clinical interventions; (B) Age at testing; (C) Follow‐up time; (D) Phenotypic findings per individual. The global Kruskal–Wallis p value is shown in the upper right corner of each plot. Asterisks in the plots denote statistically significant pairwise comparisons (*p < 0.05; **p < 0.01; ***p < 0.001). Abbreviations: OSH = outside hospital.

For interventions, the most common therapies included growth hormones, estrogen, and surgery across most cohorts. The most common surgery procedures were heart and/or vascular surgery. In addition, a subset of the CM2 [45,X/XY] cohort underwent gonadectomy for presence of ovotestes. The CM5 [45,X/XXX] cohort tended to require fewer interventions (Figure 3A, Table S2).

The TS cohort showed significant differences in age at testing across subgroups (Kruskal–Wallis, p < 0.005). To account for important puberty‐related differences in TS, the classic TS cohort was divided into a TSC‐pre‐puberty group with a median age at testing of 0.01 years (range: 0–6.6) and a TSC‐post‐puberty group with a median age of 12.4 years (range: 8.0–26.7).

The median age of testing of the four TSV del(X) individuals was 22.5 years (range: 16.8–41.6 years) and occurred later than TSC (both pre‐pubertal and post‐pubertal), TSV i(X), and TSV der(X) individuals. There was a broad distribution in the age of testing among TSM cases at our institution, with all complex mosaic subgroups (CM1–5) tending to undergo testing at younger ages compared to the TSSM cohort. Within the complex mosaic cohort, the CM5 subgroup was referred for testing at the youngest age (median age: 0.01 years, range: 0–1.8 years) (Figure 3B), while the two individuals with [45,X/XXX/XX] (CM6 subgroup) had testing done at older ages (37.3 and 45.3 years) (Table S2).

The median follow‐up duration was broadly similar across groups, with no statistically significant difference observed overall (Kruskal–Wallis, p = 0.737). The shortest follow‐up was 2.5 years (range: 0–5.7) for TSV i(X) and 1.9 years (range: 0–7.9) for CM5 (Figure 3C). Follow‐up times were otherwise comparable across the remaining groups: 8.1 years (range: 0–10.7) for TSC‐pre‐puberty, 6.6 years (range: 0–10.5) for TSC‐post‐puberty, 6.5 years (range: 2.4–7.1) for TSV del(X), 8.7 years (range: 4.1–9.0) for TSV der(X), 4.5 years (range: 0–10.6) for TSSM, 7.6 years (range: 0–13.2) for CM1, 6.3 years (range: 0.1–10.2) for CM2, 6.7 years (range: 0–9.7) for CM3, and 7.3 years (range: 2.3–9.3) for CM4.

The TSC‐pre‐puberty subgroup demonstrated a median of 6 (range: 1–10) phenotype findings per individual, whereas the TSC‐post‐puberty subgroup demonstrated a median of 9.5 (range: 5–12). The TSSM group exhibited a broad range of phenotypic findings per individual, with a median of 5 findings (range: 0–13) reported. Phenotypic burden was generally comparable across the mosaic categories, with the exception of CM5, which exhibited the fewest findings per individual of the entire cohort (Kruskal–Wallis, p = 0.094) (Figure 3D). The three TSV subgroups did not differ significantly from the TSC groups in the number of phenotypic findings per individual. However, our data suggests that the phenotype severity (i.e., the complexity of the clinical picture due to the accumulation of pathologic phenotype findings) within the TSV cohort was related to the structural abnormality of the X chromosomes (Figure 3D, Figure 4).

FIGURE 4.

FIGURE 4

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Turner syndrome (TS) Cohort Phenotype Frequencies. The TS cohort was divided into the following groups: TS classic (TSC) subgroups [pre‐puberty, post‐puberty], TS variant (TSV) subgroups [del(X), der(X), i(X)], and TS mosaic (TSM) subgroups (TSSM, CM1, CM2, CM3, CM4, CM5). Abbreviations: GU, genitourinary; MSK, musculoskeletal.

Within the TSC‐pre‐puberty subgroup, the most common phenotypes reported included short stature (76%), congenital heart defects (71%), lymphedema (71%), neck abnormalities (67%), chest abnormalities (57%), recurrent ear infections (43%), eye findings (33%), musculoskeletal findings (24%), and high arched palate (24%) (Figure 4). The TSC‐post‐puberty subgroup reported more types of phenotype findings (n = 33) compared to the TSV der(X), i(X) and del(X) cohorts which displayed 12, 16, and 19 phenotype findings, respectively (Figure 4). The most common findings within the TSC‐post‐puberty cohort were short stature (92%), ovarian failure (92%), recurrent ear infections (50%), hearing loss (50%), musculoskeletal findings (42%), neck abnormalities (42%), and vitamin D deficiency (42%). While short stature and ovarian failure were present across all the subgroups within the constitutional TS cohort (i.e., TSC and TSV cohorts), findings such as neck abnormalities, lymphedema, chest abnormalities, congenital genitourinary anomalies, and craniofacial anomalies were seen exclusively in the TSC cohort (Figure 4, Table S2). Within the TSV cohort, all individuals in the del(X) subgroup had a history of psychiatric conditions (i.e., anxiety and/or depression) and showed the highest frequency of obesity (75%) and hypertension (75%). Additionally, all three cases of the TSV der(X) TSV reported eye findings.

Across the TSM group, there was no significant difference between the average percentage of TS cell lines across the subgroups (Table S3). The TSSM cohort overall tended to have fewer phenotype findings reported (n = 28) compared to the TSC‐post‐puberty cohort (n = 33) (Figure 4). Congenital heart defects and MSK findings were present across all TSM subgroups. Only half of the individuals in the CM2 subgroup presented female sexual characteristics at birth. Short stature, ovarian failure, neck abnormalities, recurrent ear infections, hearing loss, and eye findings were also reported in most subgroups (Figure 4, Table S2).

Overall, in the TS cohort, the most common congenital heart defects seen in the cohorts were bicuspid aortic valve, coarctation of the aorta, septal defects, hypoplastic left heart syndrome, partial/total anomalous pulmonary venous return, and patent ductus arteriosus. Neck abnormalities included webbed neck, excess nuchal skin, and short/wide neck. Recurrent musculoskeletal findings were hand/foot congenital anomalies (shortened fourth metacarpals or metatarsals, clinodactyly), hypotonia, cubitus valgus, joint hypermobility, developmental dysplasia of the hips, and leg length discrepancy. The most common eye findings included strabismus, myopia, amblyopia, and hyperopia. Frequent chest abnormalities included broad chest and/or broadly spaced nipples (Table S2).

4. Discussion

Our study of the structural and numerical imbalances of sex chromosomes including the classic forms, rare variants, and mosaic cases of KS and TS is a comprehensive, data‐driven investigation at a single academic medical center over 10 years. Identification of statistically significant, nonrandom associations between genotype and phenotype could help define the pathogenesis and/or progression of SCA disorders and have key implications for enhanced diagnostic and therapeutic management.

Although tall stature has been considered one of the most common phenotypic findings in KS within the literature, we found a small subset of patients (17%, 29%, 20%, and 50% of the KSC‐neonate, KSC‐infant/child, KSM, and Other sSCA, respectively) had short stature (Völkl et al. 2006; Lanfranco et al. 2004; Bonomi et al. 2017; Groth et al. 2013). Short stature may be overlooked due to its relative infrequency and absence of typical KS features like sex developmental problems (Bahíllo‐Curieses et al. 2011). We recommend chromosome analysis for males who do not exhibit typical KS features including males demonstrating short stature. Early identification and treatment may have significant prognostic and therapeutic implications. In concordance with prior studies, the KSM cohort presented with less severe phenotypic findings compared to the KSC‐adolescent/adult cohort (Guess et al. 2024; Samplaski et al. 2014). Neurological findings, sparse body hair, tall stature, pubertal delay, and eye findings were observed in the KSC‐adolescent/adult and Other sSCA cohorts but not in KSM cohort.

Consistent with the literature, the Other sSCA cohort tended to have higher rates of congenital abnormalities (i.e., congenital heart defects, MSK findings, craniofacial anomalies) and neurological/psychosocial issues (i.e., developmental delay, learning disorders, autism spectrum disorder, neurology findings) compared to the KSC‐adolescent/adult cohort (Visootsak and Graham 2006; Frühmesser and Kotzot 2011; Spaziani et al. 2024; Tartaglia et al. 2011). Also, the Other sSCA subgroup showed statistically significant higher rates of developmental delay in comparison to the KSC and KSM cohorts. However, the Other sSCA cohort did not show infertility, azoospermia, gynecomastia, recurrent ear infections, hearing loss, congenital genitourinary anomalies, balance or coordination problems, cognitive problems, behavioral problems, or intellectual disability.

Within our TS cohort, we showed that the TSC‐pre‐puberty and TSC‐post‐puberty cohorts display the most severe phenotypes with findings like congenital heart defects, neck abnormalities, lymphedema, and chest abnormalities. We also saw a trend within the TSV cohort in which phenotype severity, or complexity of the clinical picture due to the number of accumulated pathologic clinical features, appeared to be related to the complexity of the X chromosome structural abnormality. Although the data is limited, this pattern may suggest that cytogenetics genotype analysis could offer a novel approach for predicting disease severity in TS patients.

The most common phenotypic findings in TSV del(X) cohort were psychiatric conditions (100%), ovarian failure (75%), obesity (75%), hypertension (75%), eye findings (50%), absent menstruation (50%), Hashimoto thyroiditis (50%), and vitamin D deficiency (50%). Since this group combined deletions of Xp and Xq, it is possible that our data might have missed some of the nuances of how these individual deletions affect patients. Previous studies have reported that del(Xp) individuals exhibit short stature, sexual development problems, and musculoskeletal findings (Ogata et al. 2001). Individuals with del(Xq) primarily experience abnormalities in menstruation and fertility (Mercer et al. 2013; Li et al. 2017).

The CM2 [45,X/XY] cohort showed short stature (70%), ovotestes (50%), and congenital heart defects (50%). Within the cohort, all individuals with ovotestes underwent gonadectomy with no histologic features of gonadoblastoma seen on microscopy. These findings are consistent with previous literature; however, other commonly reported features like dyslipidemia, developmental delay, and recurrent ear infections occurred at lower frequencies in our cohort (Guzewicz et al. 2021; Pleskacova et al. 2010; de Groote et al. 2013).

The CM5 [45,X/XXX] (n = 3) cohort demonstrated variable amounts of TS cell lines present on karyotype (15%, 40%, and 70%). Of note, this cohort did not exhibit short stature, which is typically considered the most common characteristic of TS.

This study has certain limitations given its retrospective design, which resulted in variable and sometimes insufficient clinical information at the time of testing and follow‐up. In addition, the age at testing and follow‐up times varied across groups. For example, the TSV del(X) group was older at time of testing (median: 22.5 years, range: 16.8–41.6 years) as compared to the TSC‐adolescents/adults and other TSV subgroups. This makes comparing the frequencies of age‐related findings like ovarian failure, dyslipidemia, hearing loss, and hypertension across groups biased due to age and follow‐up differences.

Due to the small sample sizes, phenotype frequencies observed in our cohort may not accurately reflect prevalence in larger populations. Moreover, the limited numbers, particularly for rare variants and mosaic cases, precluded achieving statistical significance, age‐stratified analyses, or reproducing trends reported in the literature.

Another limitation is related to the number of metaphase cells analyzed. Chromosome analysis was performed by analyzing 20 metaphase cells. When mosaicism was suspected, the cases were analyzed according to Turner syndrome guidelines by analyzing at least 30 metaphase cells, unless mosaicism was detected within the first 20 cells (Gravholt et al. 2024; Wolff et al. 2010). Nonetheless, analyzing fewer cells when mosaicism was not suspected may increase the risk of missing low‐level mosaicism. To mitigate this, we prioritized high‐quality metaphases, confirmed findings with complementary methods such as FISH or SNP microarray, and carefully interpreted the results within the context of clinical and phenotypic data.

More multi‐centered studies to build larger cohorts of patients with structural and numerical imbalances of sex chromosomes will help further analyze genotype–phenotype correlations, particularly for rare structural variants and mosaicism. Specifically, mosaicism of structural abnormalities and variants may play a key role in the penetrance and expression of clinical phenotypes. Developing a better understanding of how each genotype affects phenotype can result in better management and improved patient outcomes.

Author Contributions

Conceptualization: S.A.H., J.A.M.‐R., X.X., A.K.Y. Data curation: S.A.H. Formal analysis: S.A.H., J.A.M.‐R., X.X. Investigation: S.A.H., J.A.M.‐R., X.X., A.K.Y. Resources: S.A.H., J.A.M.‐R. Software: J.A.M.‐R. Visualization: S.A.H., J.A.M.‐R. Writing – original draft: S.A.H. Writing – review and editing: S.A.H., J.A.M.‐R., X.X., A.K.Y.

Funding

The authors have nothing to report.

Disclosure

The authors have nothing to report.

Ethics Statement

This study qualified for exemption per §46.104(d)(4) by the International Review Board (IRB) 240,131 on August 16, 2024. All data collected was stored securely and confidentially, and participant identities were kept anonymous.

Supporting information

Figure S1: TSV del(X) with partial deletion of chromosome X (n = 4).

Figure S2: TSV der(X) with unbalanced X‐autosome translocations (n = 3) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “TSV der(X)” in main figures.

Figure S3: TSV i(X) with unstable isochromosome due to isodicentric chromosome or presence of 2 XIST genes (n = 4) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “TSV i(X)” in main figures. (a) 46,X,i(X)(q10) (n = 2); (b) 46,X,psu idic(X)(q11.2) (n = 1); (c) 46,X,idic(X)(p21.2) (n = 1).

Figure S4: CM2 [45,X/XY] mosaic TS (n = 10) Ideogram representations with a 550‐banding resolution. Subgroup designated as “CM2 [45,X/XY]” in main figures.

Figure S5: CM3 [45,X/del(X)] mosaic TS (n = 6) Ideogram representations with a 550‐banding resolution. Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “CM3 [45,X/del(X)]” in main figures.

Figure S6: CM4 [45,X/i(X)] (n = 6) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “CM4 [45,X/i(X)]” in main figures. (a) mos 45,X/46,X,i(X)(q10) (n = 4) (b) 46,X,psu idic(X)(p11.2) [7] (n = 1); (c) mos 45,X [13]/46,X,idic(X)(q21.31) [7] (n = 1);

Table S3: TSM Cohort Average Percentage of Mosaicism.

MGG3-14-e70171-s003.docx (2MB, docx)

Table S1: mgg370171‐sup‐0002‐TableS1.xls.

MGG3-14-e70171-s002.xls (49.5KB, xls)

Table S2: mgg370171‐sup‐0003‐TableS2.xls.

MGG3-14-e70171-s001.xls (77KB, xls)

Hart, S. A. , Morales‐Rosado J. A., Xu X., and Yenamandra A. K.. 2026. “Genotype–Phenotype Correlations in Klinefelter and Turner Syndrome: A Decade of Sex Chromosome Aneuploidy Data From a Single Academic Medical Center.” Molecular Genetics & Genomic Medicine 14, no. 1: e70171. 10.1002/mgg3.70171.

Data Availability Statement

All data supporting the findings of this study are available within the paper and its Supporting Information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1: TSV del(X) with partial deletion of chromosome X (n = 4).

Figure S2: TSV der(X) with unbalanced X‐autosome translocations (n = 3) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “TSV der(X)” in main figures.

Figure S3: TSV i(X) with unstable isochromosome due to isodicentric chromosome or presence of 2 XIST genes (n = 4) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “TSV i(X)” in main figures. (a) 46,X,i(X)(q10) (n = 2); (b) 46,X,psu idic(X)(q11.2) (n = 1); (c) 46,X,idic(X)(p21.2) (n = 1).

Figure S4: CM2 [45,X/XY] mosaic TS (n = 10) Ideogram representations with a 550‐banding resolution. Subgroup designated as “CM2 [45,X/XY]” in main figures.

Figure S5: CM3 [45,X/del(X)] mosaic TS (n = 6) Ideogram representations with a 550‐banding resolution. Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “CM3 [45,X/del(X)]” in main figures.

Figure S6: CM4 [45,X/i(X)] (n = 6) Ideogram representations with a 550‐banding resolution and resulting #abnormal chromosome. Subgroup designated as “CM4 [45,X/i(X)]” in main figures. (a) mos 45,X/46,X,i(X)(q10) (n = 4) (b) 46,X,psu idic(X)(p11.2) [7] (n = 1); (c) mos 45,X [13]/46,X,idic(X)(q21.31) [7] (n = 1);

Table S3: TSM Cohort Average Percentage of Mosaicism.

MGG3-14-e70171-s003.docx (2MB, docx)

Table S1: mgg370171‐sup‐0002‐TableS1.xls.

MGG3-14-e70171-s002.xls (49.5KB, xls)

Table S2: mgg370171‐sup‐0003‐TableS2.xls.

MGG3-14-e70171-s001.xls (77KB, xls)

Data Availability Statement

All data supporting the findings of this study are available within the paper and its Supporting Information.

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