Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Phenotypic variability and management of patients with mosaic monosomy X and Y chromosome material: a case series.

BACKGROUND: we aim to discuss the origin and the differences of the phenotypic features and the management care of rare form of disorder of sex development due to Mosaic monosomy X and Y chromosome materiel. METHODS: We report our experience with patients harboring mosaic monosomy X and Y chromosome material diagnosed by blood cells karyotypes and cared for in our department from 2005 to 2022. RESULTS: We have included five infants in our study. The current average age was 8 years. In four cases, the diagnosis was still after born and it was at the age of 15 years in one case. Physical examination revealed a variable degree of virilization, ranging from a normal male phallus with unilateral ectopic gonad to ambiguous with a genital tubercle and bilateral not palpable gonads in four cases and normal female external genitalia in patient 5. Karyotype found 45, X/46, XY mosaicism in patient 1 and 2 and 45, X/46, X, der (Y) mosaicism in patient 3, 4 and 5. Three cases were assigned to male gender and two cases were assigned to female. After radiologic and histologic exploration, four patients had been explored by laparoscopy to perform gonadectomy in two cases and Mullerian derivative resection in the other. Urethroplasty was done in two cases of posterior hypospadias. Gender identity was concordant with the sex of assignment at birth in only 3 cases. CONCLUSION: Because of the phenotypic heterogeneity of this sexual disorders and the variability of its management care, then the decision should rely on a multidisciplinary team approach.

Prenatal diagnosis of a trisomy 7 mosaic case: CMA, CNV-seq, karyotyping, interphase FISH, and MS-MLPA, which technique to choose?

OBJECTIVE: This study aims to perform a prenatal genetic diagnosis of a high-risk fetus with trisomy 7 identified by noninvasive prenatal testing (NIPT) and to evaluate the efficacy of different genetic testing techniques for prenatal diagnosis of trisomy mosaicism. METHODS: For prenatal diagnosis of a pregnant woman with a high risk of trisomy 7 suggested by NIPT, karyotyping and chromosomal microarray analysis (CMA) were performed on an amniotic fluid sample. Low-depth whole-genome copy number variation sequencing (CNV-seq) and fluorescence in situ hybridization (FISH) were used to clarify the results further. In addition, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to analyze the possibility of uniparental disomy(UPD). RESULTS: Amniotic fluid karyotype analysis revealed a 46, XX result. Approximately 20% mosaic trisomy 7 was detected according to the CMA result. About 16% and 4% of mosaicism was detected by CNV-seq and FISH, respectively. MS-MLPA showed no methylation abnormalities. The fetal ultrasound did not show any detectable abnormalities except for mild intrauterine growth retardation seen at 39 weeks of gestation. After receiving genetic counseling, the expectant mother decided to continue the pregnancy, and follow-up within three months of delivery was normal. CONCLUSION: In high-risk NIPT diagnosis, a combination of cytogenetic and molecular genetic techniques proves fruitful in detecting low-level mosaicism. Furthermore, the exclusion of UPD on chromosome 7 remains crucial when NIPT indicates a positive prenatal diagnosis of trisomy 7.

Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study.

Mosaic loss of chromosome Y (mLOY) is the most common somatic alteration as men aging and may reflect genome instability. PM exposure is a major health concern worldwide, but its effects with genetic factors on mLOY has never been investigated. Here we explored the associations of PM2.5 and PM10 exposure with mLOY of 10,158 males measured via signal intensity of 2186 probes in male-specific chromosome-Y region from Illumina array data. The interactive and joint effects of PM2.5 and PM10 with genetic factors and smoking on mLOY were further evaluated. Compared with the lowest tertiles of PM2.5 levels in each exposure window, the highest tertiles in the same day, 7-, 14-, 21-, and 28-day showed a 0.005, 0.006, 0.007, 0.007, and 0.006 decrease in mLRR-Y, respectively (all P < 0.05), with adjustment for age, BMI, smoking pack-years, alcohol drinking status, physical activity, education levels, season of blood draw, and experimental batch. Such adverse effects were also observed in PM10-mLOY associations. Moreover, the unweighted and weighted PRS presented significant negative associations with mLRR-Y (both P < 0.001). Participants with high PRS and high PM2.5 or PM10 exposure in the 28-day separately showed a 0.018 or 0.019 lower mLRR-Y level [ß (95 %CI) = -0.018 (-0.023, -0.012) and - 0.019 (-0.025, -0.014), respectively, both P < 0.001], when compared to those with low PRS and low PM2.5 or PM10 exposure. We also observed joint effects of PM with smoking on exacerbated mLOY. This large study is the first to elucidate the impacts of PM2.5 exposure on mLOY, and provides key evidence regarding the interactive and joint effects of PM with genetic factors on mLOY, which may promote understanding of mLOY development, further modifying and increasing healthy aging in males.

Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.

Possible germline mosaicism in a pedigree with Treacher Collins syndrome: A case report and brief review.

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder, typically inherited as an autosomal dominant condition. Here, we report on a family in which germline mosaicism for TCS was likely present. The proband was diagnosed with TCS based on the typical clinical features and a pathogenic variant TCOF1 (c.4369_4373delAAGAA, p.K1457Efs*12). The mutation was not detected in his parents' peripheral blood DNA samples, suggesting a de novo mutation had occurred in the proband. However, a year later, the proband's mother became pregnant, and the amniotic fluid puncture revealed that the fetus carried the same mutation as the proband. Prenatal ultrasound also indicated a maxillofacial dysplasia with unilateral microtia. The mother then disclosed a previous birth history in which a baby had died of respiratory distress shortly after birth, displaying a TCS-like phenotype. Around the same time, the proband's father was diagnosed with mild bilateral conductive hearing loss. Based on array data, we concluded that the father may have had germline mosaicism for TCOF1 mutation. Our findings highlight the importance of considering germline mosaicism in sporadic de novo TCOF1 mutations when providing genetic consulting, and prenatal diagnosis is important when the proband's parents become pregnant again.

[Genetic origin analysis of regions of homozygosity in three cases].

OBJECTIVE: To explore the genetic characteristics of three fetuses with regions of homozygosity (ROH). METHODS: Three fetuses with ROH diagnosed at Nanjing Drum Tower Hospital on December 2, 2020, March 19, 2021, and May 27, 2022, respectively were selected as the study subjects. Clinical data of the fetuses were collected. Chromosomal microarray analysis (CMA) was used to detect the ROH, and tandem repeat sequences (STR)-based multiplex PCR assay was used to identify the mosaicism status in fetus 1. RESULTS: Partial maternal isodisomy (iUPD) (16) was found in fetus 1, for which trisomy rescue may be accountable. Meanwhile, the fetus also has confined placental mosaicism (CPM) but not true mosaicism. The formation mechanism of ROH for fetus 2 was identity by descent. Partial maternal iUPD (7) was found in fetus 3, which may be due to gametic recombination. CONCLUSION: The ROH of the three fetuses were inherited from both parents or the mother. Above findings suggested that it is justified to detect ROH on imprinting disorder-related chromosomes when potential uniparental disomy is suspected.

Therapeutic Management and Outcomes of Hepatoblastoma in a Pediatric Patient with Mosaic Edwards Syndrome.

The mosaic form of Edwards syndrome affects 5% of all children with Edwards syndrome. The clinical phenotype is highly variable, ranging from the full spectrum of trisomy 18 to the normal phenotype. The purpose of this publication was to present the therapeutic process in an 18-month-old girl with the mosaic form of Edwards syndrome and hepatoblastoma, against the background of other cases of simultaneous occurrence of this syndrome and hepatoblastoma described so far. It appears that this particular group of patients with hepatoblastoma and Edwards syndrome can have good outcomes, provided they do not have life-threatening cardiac or other severe defects. Due to the prematurity of our patient and the defects associated with Edwards syndrome, the child required constant multidisciplinary care, but Edwards syndrome itself was not a reason to discontinue therapy for a malignant neoplasm of the liver. Regular abdominal ultrasound examination, along with AFP testing, may be helpful in the early detection of liver tumors in children with Edwards syndrome.

Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior.

The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI influences X-linked disease penetrance: maternal transmission of the fragile X mental retardation 1 (Fmr1)-knockout (KO) allele confers 55% of total brain cells with mutant X-active, which is sufficient for behavioral penetrance, while 40% produced from paternal transmission is tolerated. Local XCI mosaicism within affected maternal Fmr1-KO mice further specifies sensorimotor versus social anxiety phenotypes depending on which distinct brain circuitry is most affected, with only a 50%-55% mutant X-active threshold determining penetrance. Thus, our results define a model of X-linked disease penetrance in females whereby distributed XCI among single cells populating brain circuitries can regulate the behavioral penetrance of an X-linked mutation.

CAG repeat mosaicism is gene specific in spinocerebellar ataxias.

Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem tissues and fetal tissues from SCA1, SCA3, and SCA7 individuals to examine somatic expansion at different stages of life. We showed that somatic mosaicism in the blood increases over time. Expansion levels are significantly different among SCAs and correlate with CAG repeat lengths. The level of expansion is greater in individuals with SCA7 who manifest disease compared to that of those who do not yet display symptoms. Brain tissues from SCA individuals have larger expansions compared to the blood. The cerebellum has the lowest mosaicism among the studied brain regions, along with a high expression of ATXNs and DNA repair genes. This was the opposite in cortices, with the highest mosaicism and lower expression of ATXNs and DNA repair genes. Fetal cortices did not show repeat instability. This study shows that CAG repeats are increasingly unstable during life in the blood and the brain of SCA individuals, with gene- and tissue-specific patterns.

Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

[Analysis of related factors influencing the detection rate of mosaic embryo and the pregnancy outcomes with mosaic embryo transfers].

Objective: To explore the related factors influencing the detection rate of mosaic embryo and the pregnancy outcomes of mosaic embryo transfer in preimplantation genetic testing for aneuploidy (PGT-A) based on next generation sequencing (NGS) technology. Methods: A retrospective study was performed to analyze the clinical data of patients in 745 PGT-A cycles from January 2019 to May 2023 at Chongqing Health Center for Women and Children, including 2 850 blastocysts. The biopsy cells were tested using NGS technology, and the embryos were divided into three groups based on the test results, namely euploid embryos, aneuploid embryos and mosaic embryos. The influence of population characteristics and laboratory-related parameters on the detection rate of mosaic embryo were analyzed, and the pregnancy outcomes of 98 mosaic embryo transfer cycles and 486 euploid embryo transfer cycles were compared during the same period, including clinical pregnancy rate and live birth rate. Results: Among the embryos tested (n=2 850), the number and proportion of euploid embryos, aneuploid embryos and mosaic embryos were 1 489 (52.2%, 1 489/2 850), 917 (32.2%, 917/2 850) and 444 (15.6%, 444/2 850), respectively. Among mosaic embryos, 245 (55.2%, 245/444) were segmental mosaic embryos, 118 (26.6%, 118/444) were whole-chromosome mosaic embryos, and 81 (18.2%, 81/444) were complex mosaic embryos. NGS technology was performed in 4 genetic testing institutions and the detection rate of mosaic embryo fluctuated from 13.5% to 27.0%. The distributions of female age, level of anti-Müllerian hormone, PGT-A indications, ovulation-inducing treatments, gonadotropin (Gn) dosage, Gn days, inner cell mass grade, trophectoderm cell grade, genetic testing institutions and developmental stage of blastocyst were significantly different among the three groups (all P<0.05). Multi-factor analysis showed that the trophectoderm cell grade and genetic testing institutions were significantly related to the detection rate of mosaic embryo; compared with the trophectoderm cell graded as A, the detection rate of mosaic embryo was significantly increased in the trophectoderm cell graded as B-(OR=1.59, 95%CI: 1.04-2.44, P=0.033); compared with genetic testing institution a, the detection rate of mosaic embryo was significantly higher (OR=2.89, 95%CI: 2.10-3.98, P<0.001) in the testing institution c. The clinical pregnancy rate and live birth rate with mosaic embryos transfer were significantly lower than those of euploid embryos transfer (clinical pregnancy rate: 51.0% vs 65.2%, P=0.008; live birth rate: 39.4% vs 53.2%, P=0.017). After adjustment for age, PGT-A indications, trophectoderm cell grade and days of embryo culture in vitro, the clinical pregnancy rate and live birth rate with mosaic embryos transfer were significantly lower than those of euploid embryos transfer (clinical pregnancy rate: OR=0.52, 95%CI: 0.32-0.83, P=0.007; live birth rate: OR=0.50, 95%CI: 0.31-0.83, P=0.007). Conclusions: The trophectoderm cell grade and genetic testing institutions are related to the detection rate of mosaic embryo. Compared with euploid embryos transfer, the clinical pregnancy rate and live birth rate with mosaic embryos transfer are significantly reduced. For infertile couple without euploid embryos, transplantable mosaic embryos could be recommended according to the mosaic ratio and mosaic type in genetic counseling to obtain the optimal pregnancy outcome.

Loss of the Y Chromosome: A Review of Molecular Mechanisms, Age Inference, and Implications for Men's Health.

Until a few years ago, it was believed that the gradual mosaic loss of the Y chromosome (mLOY) was a normal age-related process. However, it is now known that mLOY is associated with a wide variety of pathologies in men, such as cardiovascular diseases, neurodegenerative disorders, and many types of cancer. Nevertheless, the mechanisms that generate mLOY in men have not been studied so far. This task is of great importance because it will allow focusing on possible methods of prophylaxis or therapy for diseases associated with mLOY. On the other hand, it would allow better understanding of mLOY as a possible marker for inferring the age of male samples in cases of human identification. Due to the above, in this work, a comprehensive review of the literature was conducted, presenting the most relevant information on the possible molecular mechanisms by which mLOY is generated, as well as its implications for men's health and its possible use as a marker to infer age.

Prenatal detection of mosaicism for a genome wide uniparental disomy cell line in a cohort of patients: Implications and outcomes.

OBJECTIVES: To investigate the prenatal detection rate of mosaicism by SNP microarray analysis, in which an individual has not one, but two, complete genomes (sets of DNA) in their body, a normal biparental line with a Genome Wide Uniparental Disomy (GWUPD) cell line was used. METHODS: This study retrospectively examines the prenatal detection of GWUPD in a cohort of ∼90,000 prenatal specimens and ∼20,000 products of conceptions (POCs) that were studied by SNP microarray. RESULTS: In total, 25 cases of GWUPD were detected; 16 cases were detected prenatally with GWUPD (∼0.018%) and 9 POCs revealed GWUPD (0.045%). The nine POC specimens presented with placental abnormalities. The 12 amniotic fluid specimens were ascertained because of abnormal ultrasound findings. Nine of 12 pregnancies had findings consistent with Beckwith-Wiedemann syndrome or because of abnormal placentas. However, three pregnancies were detected with GWUPD of maternal origin, with less common findings and demonstrated maternal origin. Four other pregnancies showed GWUPD in a chorionic villus sample, but normal findings in amniotic fluid and apparently normal fetal development. CONCLUSIONS: This cohort with GWUPD mosaicism expands our understanding of GWUPD and has implications for prenatal care and counseling. Additional studies are necessary to understand the rarer maternal GWUPD.

Origin of pathogenic variant and mosaicism in families with a sporadic case of haemophilia B.

INTRODUCTION: Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B. AIM: The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers. METHODS: The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique. RESULTS: In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather. CONCLUSION: The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.

Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism.

BACKGROUND: Paired-like Homeobox 2B (PHOX2B) is considered the causative gene of Congenital Central Hypoventilation Syndrome (CCHS), a dominant genetic disorder characterized by impaired central respiratory control and subsequent hypoventilation during sleep. METHODS: Herein, we present a family with recurrent severe CCHS. The potential causative genetic variant was confirmed through Whole-Exome Sequencing (WES), Sanger sequencing, and droplet digital PCR (ddPCR). Furthermore, prenatal diagnosis was performed on the proband's mother at 20 weeks of her fourth pregnancy upon request. RESULTS: The proband and her brother were both carriers of the PHOX2B polyalanine expansion variant: c.744_758dupCGCGGCAGCGGCGGCGGCGGC. Sanger sequencing revealed that the proband's father had a small variant peak in the gene position, implying potential somatic mosaicism. In addition, ddPCR results showed that the proband's father had germline mosaicism, with a mosaicism proportion of 14.3%. Notably, the detect p.(Ala241[26]) variant was not detected in the fetus. CONCLUSIONS: These findings have important implications for improving genetic counseling of CCHS families as they suggest that even parents without CCHS symptoms may have somatic chimerism, necessitating careful genetic counseling and consideration of prenatal testing for subsequent pregnancies.

Improving Diagnostic Precision: Phenotype-Driven Analysis Uncovers a Maternal Mosaicism in an Individual with RYR1-Congenital Myopathy.

Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature.

BACKGROUND: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. PROBLEM: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

Tissue mosaicism following stem cell aging: blood as an exemplar.

Loss of stem cell regenerative potential underlies aging of all tissues. Somatic mosaicism, the emergence of cellular patchworks within tissues, increases with age and has been observed in every organ yet examined. In the hematopoietic system, as in most tissues, stem cell aging through a variety of mechanisms occurs in lockstep with the emergence of somatic mosaicism. Here, we draw on insights from aging hematopoiesis to illustrate fundamental principles of stem cell aging and somatic mosaicism. We describe the generalizable changes intrinsic to aged stem cells and their milieu that provide the backdrop for somatic mosaicism to emerge. We discuss genetic and nongenetic mechanisms that can result in tissue somatic mosaicism and existing methodologies to detect such clonal outgrowths. Finally, we propose potential avenues to modify mosaicism during aging, with the ultimate aim of increasing tissue resiliency.