Review

Authors: Jörg Cammenga

SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are the genetic cause of MIRAGE syndrome, ataxia-pancytopenia (ATXPC) syndrome, myeloid leukemia syndrome with monosomy 7 (MLSM7), refractory cytopenia of childhood (RCC), transient monosomy 7 in children, SAMD9L-associated autoinflammatory disease (SAAD), and a proportion of inherited aplastic anemia and bone marrow failure syndromes. The myeloid neoplasms associated with GL GOF SAMD9/SAMD9L mutations have been included in the World Health Organization (WHO) 2022 classification. The discovery of SAMD9/SAMD9L-related diseases has revealed some interesting pathobiological mechanisms, such as a high rate of primary somatic compensation, with one of the mechanisms being (transient) monosomy 7 a mechanism also described as "adaption by aneuploidy." The somatic compensation in the blood can complicate the diagnosis of SAMD9/SAMD9L-related disease when relying on hematopoietic tissues for diagnosis. Recently, GL loss-of function (LOF) mutations have been identified in older individuals with myeloid malignancies in accordance with a mouse model of SAMD9L loss that develops a myelodysplastic syndrome (MDS)-like disease late in life. The discovery of SAMD9/SAMD9L-associated syndromes has resulted in a deeper understanding of the genetics and biology of diseases/syndromes that were previously oblivious and thought to be unrelated to each other. Besides giving an overview of the literature, this review wants to also provide some practical guidance for the classification of SAMD9/SAMD9L variants that is complicated by the nonrecurrent nature of these mutations but also by the fact that both GL GOF, as well as loss-of-function mutations, have been identified.

Topics: Humans; Chromosomes, Human, Pair 7; Myelodysplastic Syndromes; Chromosome Deletion; Animals; Intracellular Signaling Peptides and Proteins; Tumor Suppressor Proteins

PubMed: 38649131
DOI: 10.1016/j.exphem.2024.104217

Authors: Laura K Conlin, Brian D Thiel, Carsten G Bonnemann...

Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.

Topics: Aneuploidy; Chimerism; Humans; Meiosis; Monosomy; Mosaicism; Polymorphism, Single Nucleotide; Sex Chromosomes; Trisomy; Uniparental Disomy

PubMed: 20053666
DOI: 10.1093/hmg/ddq003

Authors: Clémence Jacquin, Emilie Landais, Céline Poirsier...

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Topics: Intellectual Disability; Epilepsy; Chromosome Disorders; Chromosomes, Human, Pair 1; DiGeorge Syndrome; Phenotype; Muscle Hypotonia; Down Syndrome; Chromosome Deletion; Humans; Microcephaly

PubMed: 36369750
DOI: 10.1002/ajmg.a.63041

Review

Authors: A Slavotinek, L G Shaffer, S K Shapira...

We have reviewed published reports on patients with segmental aneusomy for chromosome 1p36 to help geneticists and other health professionals in the recognition of this emerging chromosomal syndrome. Terminal deletions of the short arm of chromosome 1 are associated with hypotonia and developmental delay (usually severe), growth abnormalities (growth retardation, microcephaly, obesity), and craniofacial dysmorphism with a large anterior fontanelle, prominent forehead, deep set eyes, flat nasal bridge and midface hypoplasia, ear asymmetry, a pointed chin, and orofacial clefting. Minor cardiac malformations, cardiomyopathy, seizures, and ventricular dilatation are the more common additional findings. Sensorineural hearing loss and variable ophthalmological anomalies have also been frequently observed. Although the deletions can be detected by high resolution cytogenetic studies, confirmation by fluorescence in situ hybridisation is required in most cases. The majority of deletions are maternally derived. Molecular characterisation of 1p36 deletions has been undertaken in several cases, and it is likely that this condition is a contiguous gene deletion syndrome.

Topics: Adolescent; Adult; Child; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 1; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Syndrome

PubMed: 10507720
DOI: No ID Found

Review

Authors: Francisco Álvarez-Nava, Roberto Lanes

BACKGROUND

Monosomy of the X chromosome is the most frequent genetic abnormality in human as it is present in approximately 2% of all conceptions, although 99% of these embryos are spontaneously miscarried. In postnatal life, clinical features of Turner syndrome may include typical dysmorphic stigmata, short stature, sexual infantilism, and renal, cardiac, skeletal, endocrine and metabolic abnormalities.

MAIN TEXT

Turner syndrome is due to a partial or total loss of the second sexual chromosome, resulting in the development of highly variable clinical features. This phenotype may not merely be due to genomic imbalance from deleted genes but may also result from additive influences on associated genes within a given gene network, with an altered regulation of gene expression triggered by the absence of the second sex chromosome. Current studies in human and mouse models have demonstrated that this chromosomal abnormality leads to epigenetic changes, including differential DNA methylation in specific groups of downstream target genes in pathways associated with several clinical and metabolic features, mostly on autosomal chromosomes. In this article, we begin exploring the potential involvement of both genetic and epigenetic factors in the origin of X chromosome monosomy. We review the dispute between the meiotic and post-zygotic origins of 45,X monosomy, by mainly analyzing the findings from several studies that compare gene expression of the 45,X monosomy to their euploid and/or 47,XXX trisomic cell counterparts on peripheral blood mononuclear cells, amniotic fluid, human fibroblast cells, and induced pluripotent human cell lines. From these studies, a profile of epigenetic changes seems to emerge in response to chromosomal imbalance. An interesting finding of all these studies is that methylation-based and expression-based pathway analyses are complementary, rather than overlapping, and are correlated with the clinical picture displayed by TS subjects.

CONCLUSIONS

The clarification of these possible causal pathways may have future implications in increasing the life expectancy of these patients and may provide informative targets for early pharmaceutical intervention.

Topics: Chromosomes, Human, X; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Monosomy; Trisomy; Turner Syndrome

PubMed: 29636833
DOI: 10.1186/s13148-018-0477-0

Authors: Myriam Ben Fredj, Marwa Messaoud, Sabrine Ben Youssef...

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.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Chromosomes, Human, X; Chromosomes, Human, Y; Disorders of Sex Development; Karyotyping; Monosomy; Mosaicism; Phenotype; Turner Syndrome

PubMed: 38715086
DOI: 10.1186/s13052-024-01618-9

Review

Authors: Catherine Turleau

Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18. The incidence is estimated to be about 1:50,000 live-born infants. In the commonest form of the disorder, the dysmorphic syndrome is very moderate and non-specific. The main clinical features are short stature, round face with short philtrum, palpebral ptosis and large ears with detached pinnae. Intellectual deficiency is mild to moderate. A small subset of patients, about 10-15 percent of cases, present with severe brain/facial malformations evocative of holoprosencephaly spectrum disorders. In two-thirds of the cases, the 18p- syndrome is due to a mere terminal deletion occurring de novo, in one-third the following are possible: a de novo translocation with loss of 18p, malsegregation of a parental translocation or inversion, or a ring chr18. Parental transmission of the 18p- syndrome has been reported. Cytogenetic analysis is necessary to make a definite diagnosis. Recurrence risk for siblings is low in de novo deletions and translocations, but is significant if a parental rearrangement is present. Deletion 18p can be detected prenatally by amniocentesis or chorionic villus sampling and cytogenetic testing. Differential diagnosis may include a wide number of syndromes with short stature and mild intellectual deficiency. In young children, deletion 18p syndrome may be vaguely evocative of either Turner syndrome or trisomy 21. No specific treatment exists but speech therapy and early educational programs may help to improve the performances of the children. Except for the patients with severe brain malformations, the life expectancy does not seem significantly reduced.

Topics: Abnormalities, Multiple; Chromosome Disorders; Chromosomes, Human, Pair 18; Diagnosis, Differential; Face; Female; Genetic Counseling; Genotype; Holoprosencephaly; Humans; Incidence; Intellectual Disability; Male; Monosomy; Phenotype; Prenatal Diagnosis; Prognosis; Sex Distribution

PubMed: 18284672
DOI: 10.1186/1750-1172-3-4

Review

Authors: Toshiya Inaba, Hiroaki Honda, Hirotaka Matsui...

Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. (sterile α motif domain 9) and (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in -deficient mice over their lifetime, / are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. (enhancer of zeste homolog 2) and (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to /, loss of or likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).

Topics: Animals; Chromosome Deletion; Chromosomes, Human, Pair 7; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes

PubMed: 29615405
DOI: 10.1182/blood-2017-12-822262

Review

Authors: Andrew R Mitz, Luigi Boccuto, Audrey Thurm...

Chromosome 22q13.3 deletion (Phelan-McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS-SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS-SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS-SHANK3 related and PMS-SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype.

Topics: Humans; Nerve Tissue Proteins; Chromosome Disorders; Chromosome Deletion; Phenotype; Chromosomes, Human, Pair 22; Transcription Factors

PubMed: 38414139
DOI: 10.1111/cge.14503

Review

Authors: I M Hann

Topics: Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 7; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Monosomy; Myelodysplastic Syndromes

PubMed: 1519966
DOI: 10.1136/adc.67.7.962