Talk:Abnormal Development - Genetic

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Cite this page: Hill, M.A. (2019, June 16) Embryology Abnormal Development - Genetic. Retrieved from


Removed International Classification of Diseases 10 Entries

The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).

Chromosomal abnormalities, not elsewhere classified (Q90-Q99) Q90 Down's syndrome  ICD-11 - LD40.0 Complete trisomy 21 Q90.0 Trisomy 21, meiotic nondisjunction Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction) Q90.2 Trisomy 21, translocation Q90.9 Down's syndrome, unspecified Trisomy 21 NOS Q91 Edwards' syndrome and Patau's syndrome LD40.2 Complete trisomy 18

Q91.0 Trisomy 18, meiotic nondisjunction Q91.1 Trisomy 18, mosaicism (mitotic nondisjunction) Q91.2 Trisomy 18, translocation Q91.3 Edwards' syndrome, unspecified Q91.4 Trisomy 13, meiotic nondisjunction

LD40.1 Complete trisomy 13

Q91.5 Trisomy 13, mosaicism (mitotic nondisjunction) Q91.6 Trisomy 13, translocation Q91.7 Patau's syndrome, unspecified Q92 Other trisomies and partial trisomies of the autosomes, not elsewhere classified Incl.: unbalanced translocations and insertions Excl.: trisomies of chromosomes 13, 18, 21 (Q90-Q91) Q92.0 Whole chromosome trisomy, meiotic nondisjunction Q92.1 Whole chromosome trisomy, mosaicism (mitotic nondisjunction) Q92.2 Major partial trisomy Whole arm or more duplicated. Q92.3 Minor partial trisomy Less than whole arm duplicated. Q92.4 Duplications seen only at prometaphase Q92.5 Duplications with other complex rearrangements Q92.6 Extra marker chromosomes Q92.7 Triploidy and polyploidy

LD42.0 Triploidy - A disease caused by one additional set of chromosomes, for a total of 69 chromosomes. Triploidy can present with albuminuria, edema, or hypertension in the mother. The fetus may present with microcephaly and a placenta that is enlarged and filled with cysts in the case of extra maternally inherited chromosomes, while extra paternally inherited chromosomes cause severe growth problems, an enlarged head, and a small placenta that does not have cysts. Non-mosaic triploidy is highly lethal, and is rarely observed in live births. Confirmation is through observation of an additional set of chromosomes by karyotyping.

LD42.1 Tetraploidy - A disease caused by two additional sets of chromosomes, for a total of 92 chromosomes. This disease commonly results in spontaneous abortion during the first trimester. Live births of tetraploidy individuals are very rare. These cases are characterized by facial dysmorphism, severely delayed growth and developmental delay. Confirmation is through observation of two additional set of chromosomes by karyotyping.

LD45 Uniparental disomies - Any disease caused by the inheritance of two homologous copies of a chromosome from one parent, and none from the other parent. Confirmation is by observation of identical chromosomes pairs by genetic testing.

Q92.8 Other specified trisomies and partial trisomies of autosomes Q92.9 Trisomy and partial trisomy of autosomes, unspecified Q93 Monosomies and deletions from the autosomes, not elsewhere classified Q93.0 Whole chromosome monosomy, meiotic nondisjunction Q93.1 Whole chromosome monosomy, mosaicism (mitotic nondisjunction) Q93.2 Chromosome replaced with ring or dicentric Q93.3 Deletion of short arm of chromosome 4 Wolff-Hirschorn syndrome Q93.4 Deletion of short arm of chromosome 5 Cri-du-chat syndrome Q93.5 Other deletions of part of a chromosome Angelman syndrome Q93.6 Deletions seen only at prometaphase Q93.7 Deletions with other complex rearrangements Q93.8 Other deletions from the autosomes Q93.9 Deletion from autosomes, unspecified Q95 Balanced rearrangements and structural markers, not elsewhere classified Incl.: Robertsonian and balanced reciprocal translocations and insertions Q95.0 Balanced translocation and insertion in normal individual Q95.1 Chromosome inversion in normal individual Q95.2 Balanced autosomal rearrangement in abnormal individual Q95.3 Balanced sex/autosomal rearrangement in abnormal individual Q95.4 Individuals with marker heterochromatin Q95.5 Individuals with autosomal fragile site Q95.8 Other balanced rearrangements and structural markers Q95.9 Balanced rearrangement and structural marker, unspecified Q96 Turner's syndrome Excl.: Noonan's syndrome (Q87.1) Q96.0 Karyotype 45,X Q96.1 Karyotype 46,X iso (XQ) Q96.2 Karyotype 46,X with abnormal sex chromosome, except iso (XQ) Q96.3 Mosaicism, 45,X/46,XX or XY Q96.4 Mosaicism, 45,X/other cell line(s) with abnormal sex chromosome Q96.8 Other variants of Turner's syndrome Q96.9 Turner's syndrome, unspecified

LD50.0 Turner syndrome - Karyotype missing one X chromosome (45, X0 or 45,XO/46,XX mosaicism) ; gonads: ovaries (streak); phenotype female with short stature, amenorrhea (hypergonadotrophic hypogonadism), absence of sexual development, webbed neck, low set ears, posterior hairline, widely-spaced nipples, short fourth metacarpals, and increased carrying angle at the elbow (cubitus valgus). Often associated with renal, cardiac and ocular abnormalities.

Q97 Other sex chromosome abnormalities, female phenotype, not elsewhere classified Excl.: Turner's syndrome (Q96.-) Q97.0 Karyotype 47,XXX

LD50.1 Karyotype 47,XXX - Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). Most individuals are only mildly affected or asymptomatic, the most common physical features including tall stature, epicanthal folds, hypotonia and clinodactyly, with seizures, renal and genitourinary abnormalities, and premature ovarian failure being also associated findings.

Q97.1 Female with more than three X chromosomes Q97.2 Mosaicism, lines with various numbers of X chromosomes Q97.3 Female with 46,XY karyotype Q97.8 Other specified sex chromosome abnormalities, female phenotype Q97.9 Sex chromosome abnormality, female phenotype, unspecified Q98 Other sex chromosome abnormalities, male phenotype, not elsewhere classified Q98.0 Klinefelter's syndrome karyotype 47,XXY

LD50.3 Klinefelter syndrome - Klinefelter syndrome defines a group of chromosomal disorders in which there is at least one extra X chromosome compared with the normal 46,XY male karyotype. The effects on physical features and on physical and cognitive development increase with the number of extra X's, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15-16 points, with language most affected, particularly expressive language skills.

LD50.30 Klinefelter syndrome with karyotype 47,XXY, regular - Karyotype 47 XXY; gonads: testes (hypogonadism) small and firm with decreased spermatogenesis ; phenotype male with associated congenital abnormalities (decreased virilization due to decreased testosterone production, long arms and legs, short trunk, psychosocial problems)

LD50.31 Klinefelter syndrome, male with more than two X chromosomes - A disease affecting males, caused by the presence of more than two X chromosomes in each cell. This disease is characterized by impaired sexual development, intellectual disability, distinctive facial features, skeletal abnormalities, poor coordination, and severe problems with speech. This disease may be differentiated from classic Klinefelter syndrome by increased severity of symptoms. Confirmation is through observation of more than two X chromosomes by karyotyping.

Q98.1 Klinefelter's syndrome, male with more than two X chromosomes Q98.2 Klinefelter's syndrome, male with 46,XX karyotype Q98.3 Other male with 46,XX karyotype Q98.4 Klinefelter's syndrome, unspecified Q98.5 Karyotype 47,XYY Q98.6 Male with structurally abnormal sex chromosome Q98.7 Male with sex chromosome mosaicism Q98.8 Other specified sex chromosome abnormalities, male phenotype Q98.9 Sex chromosome abnormality, male phenotype, unspecified Q99 Other chromosome abnormalities, not elsewhere classified Q99.0 Chimera 46,XX/46,XY Chimera 46,XX/46,XY true hermaphrodite Q99.1 46,XX true hermaphrodite 46,XX with streak gonads 46,XY with streak gonads Pure gonadal dysgenesis Q99.2 Fragile X chromosome Fragile X syndrome

LD55 Fragile X chromosome - Fragile X syndrome is a rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features. Prevalence is estimated at approximately 1/ 2,500 (prevalence of the full mutation allele) to 1/ 4,000 (prevalence of symptomatic cases) for both genders.

Q99.8 Other specified chromosome abnormalities Q99.9 Chromosomal abnormality, unspecified

JA02.0 Complete hydatidiform mole - A condition caused by the over-production of cells arising into the placenta during pregnancy. This condition is characterized by a pregnancy with abnormal placental growth in which the chorionic villi become hydropic, slight to severe trophoblast proliferation and invasion of the uterine tissue within 10-16 weeks after conception, a placental mass, 25-30% theca lutein cysts, 15-20% persistent trophoblastic disease, 50% uterine size for dates, and vaginal bleeding, nausea, or vomiting. This condition leads to an absent fetus.

JA02.1 Incomplete or partial hydatidiform mole - A condition caused by the over-production of cells arising into the placenta during pregnancy. This condition is characterized by a pregnancy with abnormal placental growth in which the chorionic villi become hydropic, slight to moderate trophoblast proliferation and invasion of the uterine tissue within 10-16 weeks after conception, a placental mass, theca lutein cysts, 1-5% persistent trophoblastic disease, small uterine size for dates, and vaginal bleeding, nausea, or vomiting. This condition leads to some fetal development and a missed abortion.

Trophoblastic neoplasms

2C75.0 Malignant trophoblastic neoplasms of placenta

ICD-10 Code: Chromosomal abnormalities, not elsewhere classified

A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved?

Dev Biol. 2019 Mar 1;447(1):3-13. doi: 10.1016/j.ydbio.2018.01.014. Epub 2018 Jan 31.

Tšuiko O1, Jatsenko T2, Parameswaran Grace LK3, Kurg A4, Vermeesch JR5, Lanner F6, Altmäe S7, Salumets A8. Author information Abstract The journey of embryonic development starts at oocyte fertilization, which triggers a complex cascade of events and cellular pathways that guide early embryogenesis. Recent technological advances have greatly expanded our knowledge of cleavage-stage embryo development, which is characterized by an increased rate of whole-chromosome losses and gains, mixoploidy, and atypical cleavage morphokinetics. Embryonic aneuploidy significantly contributes to implantation failure, spontaneous miscarriage, stillbirth or congenital birth defects in both natural and assisted human reproduction. Essentially, early embryo development is strongly determined by maternal factors. Owing to considerable limitations associated with human oocyte and embryo research, the use of animal models is inevitable. However, cellular and molecular mechanisms driving the error-prone early stages of development are still poorly described. In this review, we describe known events that lead to aneuploidy in mammalian oocytes and preimplantation embryos. As the processes of oocyte and embryo development are rigorously regulated by multiple signal-transduction pathways, we explore the putative role of signaling pathways in genomic integrity maintenance. Based on the existing evidence from human and animal data, we investigate whether critical early developmental pathways, like Wnt, Hippo and MAPK, together with distinct DNA damage response and DNA repair pathways can be associated with embryo genomic instability, a question that has, so far, remained largely unexplored. Copyright © 2018 Elsevier Inc. All rights reserved. KEYWORDS: Aneuploidy; Chromosomal instability; Molecular signaling; Preimplantation embryo PMID: 29391166 DOI: 10.1016/j.ydbio.2018.01.014


The Impact of Sperm and Egg Donation on the Risk of Pregnancy Complications

Am J Perinatol. 2018 Jul 21. doi: 10.1055/s-0038-1667029. [Epub ahead of print]

Bartal MF1, Sibai BM2, Bart Y1, Shina A1, Mazaki-Tovi S1, Eisen IS3, Hendler I1, Baum M1, Schiff E1.

Abstract OBJECTIVE:  The aim of this study was to evaluate obstetric outcomes in relation to the extent of donor sperm exposure with and without egg donation. METHODS:  This is a retrospective cohort study in a single tertiary care center. All women with a singleton pregnancy who conceived following sperm donation (SD) were included. Obstetrics and neonatal outcomes for pregnancies following single SD were compared with pregnancies following repeat SD from the same donor. In a secondary analysis, we compared pregnancy outcomes among three modes of assisted reproductive technology (intrauterine insemination [IUI-SD], in vitro fertilization [IVF-SD], and IVF sperm + egg donation [IVF-SD + ED]). RESULTS:  A total of 706 pregnant women met the inclusion criteria, 243 (34.4%) following the first SD and 463 (65.6%) following repeat donations. Compared with repeat SDs, single donation was not associated with higher rates of preterm delivery (12.8 vs. 12.7%, respectively, p = 0.99), preeclampsia (7.0 vs. 6.9%, p = 0.999), and intrauterine growth restriction (4.1 vs. 3.9%, p = 0.88). Pregnancies following IVF-SD + ED had increased risk for preeclampsia (adjusted odds ratio [AOR], 3.1; 95% confidence interval [CI], 1.5-6.6), preterm labor (AOR, 2.4; 95% CI, 1.1-5.4), and cesarean section (AOR, 2.1; 95% CI, 1.0-4.3) compared with IUI-SD and IVF-SD. CONCLUSION:  The extent of donor sperm exposure did not correlate with obstetrics complications, but double gamete donation was associated with increased risk for preeclampsia, preterm labor, and cesarean section. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PMID: 30031370 DOI: 10.1055/s-0038-1667029

Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE

Eur J Hum Genet. 2018 Jan 12. doi: 10.1038/s41431-017-0077-z. [Epub ahead of print]

De Wert G1, Heindryckx B2, Pennings G3, Clarke A4, Eichenlaub-Ritter U5, van El CG6, Forzano F7, Goddijn M8, Howard HC9, Radojkovic D10, Rial-Sebbag E11, Dondorp W12, Tarlatzis BC13, Cornel MC6; European Society of Human Genetics and the European Society of Human Reproduction and Embryology.


Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns. PMID: 29326429 DOI: 10.1038/s41431-017-0077-z


Mechanisms of Aneuploidy in Human Eggs

Trends Cell Biol. 2017 Jan;27(1):55-68. doi: 10.1016/j.tcb.2016.09.002. Epub 2016 Oct 20.

Webster A1, Schuh M2. Author information Abstract Eggs and sperm develop through a specialized cell division called meiosis. During meiosis, the number of chromosomes is reduced by two sequential divisions in preparation for fertilization. In human female meiosis, chromosomes frequently segregate incorrectly, resulting in eggs with an abnormal number of chromosomes. When fertilized, these eggs give rise to aneuploid embryos that usually fail to develop. As women become older, errors in meiosis occur more frequently, resulting in increased risks of infertility, miscarriage, and congenital syndromes, such as Down's syndrome. Here, we review recent studies that identify the mechanisms causing aneuploidy in female meiosis, with a particular emphasis on studies in humans. Copyright © 2016 Elsevier Ltd. All rights reserved. KEYWORDS: aging; aneuploidy; chromosome segregation; human fertility; meiosis; oocyte PMID: 27773484 DOI: 10.1016/j.tcb.2016.09.002

Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis

Cell. 2017 Mar 9;168(6):977-989.e17. doi: 10.1016/j.cell.2017.02.002. Epub 2017 Mar 2.

Wang S1, Hassold T2, Hunt P2, White MA3, Zickler D4, Kleckner N5, Zhang L6.


Meiosis is the cellular program that underlies gamete formation. For this program, crossovers between homologous chromosomes play an essential mechanical role to ensure regular segregation. We present a detailed study of crossover formation in human male and female meiosis, enabled by modeling analysis. Results suggest that recombination in the two sexes proceeds analogously and efficiently through most stages. However, specifically in female (but not male), ∼25% of the intermediates that should mature into crossover products actually fail to do so. Further, this "female-specific crossover maturation inefficiency" is inferred to make major contributions to the high level of chromosome mis-segregation and resultant aneuploidy that uniquely afflicts human female oocytes (e.g., giving Down syndrome). Additionally, crossover levels on different chromosomes in the same nucleus tend to co-vary, an effect attributable to global per-nucleus modulation of chromatin loop size. Maturation inefficiency could potentially reflect an evolutionary advantage of increased aneuploidy for human females. PMID: 28262352 PMCID: PMC5408880 DOI: 10.1016/j.cell.2017.02.002


Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997-2009

Am J Med Genet A. 2015 May;167A(5):1071-81. doi: 10.1002/ajmg.a.36865. Epub 2015 Feb 25.

Michalski AM1, Richardson SD, Browne ML, Carmichael SL, Canfield MA, VanZutphen AR, Anderka MT, Marshall EG, Druschel CM.


A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male-female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997-2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification.

PMID 25711982


Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling


Background: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, characterized by cardiovascular defects such as interrupted aortic arch, outflow tract defects, thymus and parathyroid hypo- or aplasia, and cleft palate. Heterozygosity of Tbx1, the mouse homolog of the candidate TBX1 gene, results in mild defects dependent on genetic background, whereas complete inactivation results in severe malformations in multiple tissues. Results: The loss of function of two Sprouty genes, which encode feedback antagonists of receptor tyrosine kinase (RTK) signaling, phenocopy many defects associated with 22q11DS in the mouse. The stepwise reduction of Sprouty gene dosage resulted in different phenotypes emerging at specific steps, suggesting that the threshold up to which a given developmental process can tolerate increased RTK signaling is different. Tbx1 heterozygosity significantly exacerbated the severity of all these defects, which correlated with a substantial increase in RTK signaling. Conclusions: Our findings suggest that TBX1 functions as an essential component of a mechanism that protects the embryo against perturbations in RTK signaling that may lead to developmental defects characteristic of 22q11DS. We propose that genetic factors that enhance RTK signaling ought to be considered as potential genetic modifiers of this syndrome. Developmental Dynamics, 2012. © 2012 Wiley Periodicals, Inc.


An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening

Clin Exp Reprod Med. 2011 Sep;38(3):126-34. Epub 2011 Sep 30.

Chang LJ, Chen SU, Tsai YY, Hung CC, Fang MY, Su YN, Yang YS. Source Department of Obstetrics and Gynecology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. Abstract Preimplantation genetic diagnosis (PGD) is gradually widely used in prevention of gene diseases and chromosomal abnormalities. Much improvement has been achieved in biopsy technique and molecular diagnosis. Blastocyst biopsy can increase diagnostic accuracy and reduce allele dropout. It is cost-effective and currently plays an important role. Whole genome amplification permits subsequent individual detection of multiple gene loci and screening all 23 pairs of chromosomes. For PGD of chromosomal translocation, fluorescence in-situ hybridization (FISH) is traditionally used, but with technical difficulty. Array comparative genomic hybridization (CGH) can detect translocation and 23 pairs of chromosomes that may replace FISH. Single nucleotide polymorphisms array with haplotyping can further distinguish between normal chromosomes and balanced translocation. PGD may shorten time to conceive and reduce miscarriage for patients with chromosomal translocation. PGD has a potential value for mitochondrial diseases. Preimplantation genetic haplotyping has been applied for unknown mutation sites of single gene disease. Preimplantation genetic screening (PGS) using limited FISH probes in the cleavage-stage embryo did not increase live birth rates for patients with advanced maternal age, unexplained recurrent abortions, and repeated implantation failure. Polar body and blastocyst biopsy may circumvent the problem of mosaicism. PGS using blastocyst biopsy and array CGH is encouraging and merit further studies. Cryopreservation of biopsied blastocysts instead of fresh transfer permits sufficient time for transportation and genetic analysis. Cryopreservation of embryos may avoid ovarian hyperstimulation syndrome and possible suboptimal endometrium.

PMID 22384431


Polymorphic cis- and trans-regulation of human gene expression

PLoS Biol. 2010 Sep 14;8(9). pii: e1000480.

Cheung VG, Nayak RR, Wang IX, Elwyn S, Cousins SM, Morley M, Spielman RS.

Howard Hughes Medical Institute, Philadelphia, Pennsylvania, USA. Abstract Expression levels of human genes vary extensively among individuals. This variation facilitates analyses of expression levels as quantitative phenotypes in genetic studies where the entire genome can be scanned for regulators without prior knowledge of the regulatory mechanisms, thus enabling the identification of unknown regulatory relationships. Here, we carried out such genetic analyses with a large sample size and identified cis- and trans-acting polymorphic regulators for about 1,000 human genes. We validated the cis-acting regulators by demonstrating differential allelic expression with sequencing of transcriptomes (RNA-Seq) and the trans-regulators by gene knockdown, metabolic assays, and chromosome conformation capture analysis. The majority of the regulators act in trans to the target (regulated) genes. Most of these trans-regulators were not known to play a role in gene expression regulation. The identification of these regulators enabled the characterization of polymorphic regulation of human gene expression at a resolution that was unattainable in the past.

PMID 20856902