Chromosomal mosaicism refers to the presence of two or more genetically distinct cell lines within an individual derived from a single zygote. The clinical expression varies widely depending on the proportion and distribution of abnormal cells.
To evaluate the spectrum, clinical presentation, and outcomes of chromosomal mosaicism in individuals with suspected chromosomal abnormalities at a tertiary care center.
This observational study included 308 individuals with suspected chromosomal disorders evaluated between January 2024 and March 2026. Peripheral blood samples were collected and cultured using standard cytogenetic techniques. Karyotyping was performed using G-banding.
Chromosomal mosaicism was identified in 9 cases (2.9%). The majority involved sex chromosome mosaicism, predominantly mosaic Turner syndrome variants. Common clinical indications included primary amenorrhea and short stature. Structural abnormalities of the X chromosome were also observed. One case of mosaic trisomy 21 and one case of 45,X/46,XY mosaicism were identified. Mosaic cases generally exhibited milder or incomplete phenotypic features compared to classical syndromic presentations.
Chromosomal mosaicism is associated with variable and often attenuated clinical manifestations. Low-level mosaicism tends to correlate with better clinical outcomes and survival. Early detection is important for appropriate management and genetic counselling. Mosaic cases, particularly when identified prenatally, may have favourable prognostic implications.
Chromosomal mosaicism is defined as the presence of two or more genetically distinct cell populations within a single individual arising from a single fertilised egg. This phenomenon results from postzygotic genetic alterations and contributes to a wide range of clinical conditions, spanning from localised developmental anomalies to systemic genetic disorders and malignancies. The phenotypic expression of mosaicism depends on several factors, including the timing of the mutational event during embryogenesis, the proportion of abnormal cells, and their distribution across tissues. Mosaicism may involve somatic cells, germ cells, or both, and is broadly classified into somatic mosaicism, germline mosaicism, and combined (gonosomal) mosaicism.
Clinical features of mosaicism frequently manifest as asymmetrical tissue development (e.g., focal cortical dysplasia or segmental hypertrophy), patchy cutaneous pigmentation along lines of Blaschko, and localized vascular malformations.
| Sn | Mechanism | Origin | Key feature |
|---|---|---|---|
| 1 | De novo Alteration | Post Zygotic | Errors in mitosis (nondisjunction). |
| 2 | Nullizygosity | Loss of function | Second hit leaves a cell line with zero active allele |
| 3 | Epigenetic mosaicism | functional | Genome is same, but expression is 'on' or 'off' |
| 4 | Rescue (loss) | corrective | Extra chromosome of an trisomic embryo lost to survive |
| 5 | Reversion | corrective | A 'back-mutation' restores normal function to a cell line. |
Mosaic manifestations of Mendelian disorders can be subgrouped into: 1) Mosaicism for lethal mutations (survives only in mosaic state); 2) Mosaicism for mutations known in autosomal-dominant/X-linked disorders (e.g., NF1 at 25.33% and NF2 at 6.5% as somatic mosaicism [1]); and 3) Rare mosaicism resulting in segmental aggravation. In chromosomal mosaicism, constitutional gain or loss of chromosomes such as 13, 18, 21, and X can occur in mosaic form [2]. Mosaicism for partial X deletion and normal X is frequently observed in primary amenorrhea and infertility. Parameters like maternal age [3], consanguinity [4,5], socioeconomic status [6,7], and ethnicity [8] influence chromosomal abnormalities. Somatic selection over time favors normal cell lines in rapidly dividing tissues, often reducing clinical morbidity [9,10]. Conventional karyotyping remains a widely accessible, essential diagnostic tool in resource-limited settings.
After obtaining institutional ethical clearance, this observational study was conducted in a cohort of 308 participants presenting with suspected chromosomal disorders from January 2024 to March 2026. Peripheral blood samples were collected in heparinized vials following informed consent and demographic profiling. Lymphocyte cultures were incubated for 72 hours, followed by colcemid arrest, hypotonic treatment, fixation, and slide preparation. G-banding was performed using Giemsa stain. Karyotype analysis was carried out under a Carl Zeiss microscope with an automated imaging system (300-850 band resolution). In suspected mosaic cases with multiple cell lines, more than 50 metaphases were analyzed to confirm the clonal proportion.
Chromosomal mosaicism was identified in 9 cases (2.9% of the 308 suspected individuals). Four patients presented with primary amenorrhea, three with short stature, one with multiple congenital anomalies, and one with micropenis.
A 4-year-old female presented with short stature (height-for-age -2.8 SD), microcephaly (head circumference-for-age -3.0 SD), and low vitamin D levels (15.7 ng/mL). Karyotype revealed: mos 46,X,del(X)(q26)[14]/46,XX[46].
A 16-year-old female presented with primary amenorrhea, high-arched palate, widely spaced nipples, cubitus valgus, bilateral short 4th metacarpals, aortic murmur, hypoplastic uterus (3 x 1.2 x 0.4 cm3), elevated gonadotropins (LH 42.49 mIU/mL, FSH 193.57 mIU/mL). Karyotyping showed mos 45,X[55]/46,X,+mar[5] (Figure 1), with MLPA confirming absence of SRY gene material.
A 25-year-old female presenting with primary amenorrhea, Tanner stage III breast and pubic hair, and infantile uterus with few ovarian follicles on USG. Karyotype was mos 45,X[4]/46,XX[48].
A 25-year-old female with primary amenorrhea, hypoplastic uterus (volume 10.6 cc), and normal gonadotropins. Karyotype demonstrated mos 46,XX,del(X)(q27-q28)[25]/46,XX[48].
A 25-year-old female presenting with primary amenorrhea, Tanner stage III development, infantile hypoplastic uterus (2.0 x 1.0 x 2.2 cm3), elevated gonadotropins (FSH 53.6 mIU/mL, LH 29.1 mIU/mL). Karyotype was mos 46,XX,del(X)(q26-ter)[4]/46,XX[46].
A male child presenting with micropenis, bilateral palpable testes, and low testosterone (18.11 ng/dL). Karyotype showed mos 45,X[20]/46,XY[30] (mixed gonadal dysgenesis). Testosterone replacement was initiated with surveillance for gonadoblastoma.
A male neonate (birth weight 2425 g, born at 33 weeks via LSCS to a 29-year-old mother with gestational hypothyroidism) presenting with bilateral undescended testes, 'double bubble' sign on abdominal X-ray, duodenal atresia type 1, non-rotation of large bowel, and dextrocardia. Exploratory laparotomy with Kimura duodeno-duodenostomy was performed. Karyotype revealed mos 47,XY,+21[20]/46,XY[30] (mosaic trisomy 21).
A 7-year-old female presenting with short stature, growth restriction, and patchy cutaneous hyperpigmentation following lines of Blaschko on the elbow. Karyotype showed mos 46,XX,del(X)(q26)[15]/46,XX[39] (Figure 2).
Chromosomal mosaicism was identified in 2.9% of evaluated individuals, consistent with reported frequencies (~2.4% in Cook et al. [10]). Sex chromosome mosaicism, particularly mosaic Turner syndrome variants and X-structural deletions, predominated. Mosaic cases presented with an attenuated, milder phenotype compared to full monosomy X, reflecting the modifying protective influence of the normal 46,XX cell lineage [11].
In 45,X/46,XY mosaicism, mixed gonadal dysgenesis carries a heightened risk of gonadoblastoma and dysgerminoma, necessitating multidisciplinary care (pediatric endocrinology, pediatric surgery/urology, and clinical genetics) and potential prophylactic gonadectomy [12]. Autosomal mosaicism (such as mosaic trisomy 21 in Case 7) is compatible with live birth and variable syndromic severity. Cutaneous pigmentary alterations along Blaschko lines (Case 8) provide clinical indicators of underlying somatic chromosomal mosaicism.
Chromosomal mosaicism represents an important clinical subgroup with highly variable and often attenuated phenotypes. Sex chromosome mosaicism forms the predominant category in clinical cytogenetics. Low-level mosaicism correlates with better functional preservation and survival. Accurate karyotyping and molecular adjuncts are vital for individualized risk stratification, endocrine management, and genetic counseling.
The author thanks Nursing Officer Ms. Renu and Lab Technician Mr. Chetan for their help throughout this study. The author also extends regards to the family members who continue to participate in clinical cytogenetic research.