3. Temporal trends in the birth prevalence of selected congenital malformations in the birth defects monitoring program/commission on professional and hospital activities, 1979-1989

The problem of differential prevalence of congenital malformation and reproductive losses in Ukrainian populations becomes especially relevant in the context of increasing the impact of environmental and genetic and demographic factors that can influence their gene pool. The purpose of the study is to determine, during long-term monitoring, the statistically significant differences between the rural populations of Kherson oblast on the incidence of birth defects, involuntary miscarriages and stillbirths, in order to further identify the causes of detected heterogeneity. In calculating the frequency of these indicators in urban and rural populations, the materials of the regional medical-statistical register (medical form 21, 13, 49) are used. The statistical computation of the results obtained (calculation of confidence intervals and the reliability of the differences) was carried out using STATISTICA and Microsoft Excel 9-2000 programs. It has been established that there are significant differences between urban and rural populations in the prevalence of congenital malformations and reproductive losses. In Kherson, for the period of 2000–2013, the average incidence of developmental defects (37.8±11.3‰) and stillbirths (8.2±1.1‰) significantly exceeded similar rates in rural populations (respectively 23.9±1.4‰ and 4.8±0.6‰). However, in rural populations, the incidence of involuntary miscarriages was significantly higher (31.2 ± 1.9 ‰) than in the oblast center (18.9 ± 2.1 ‰). In addition, according to these indicators there is a significant differentiation between rural populations. The prevalence of birth defects in infants in the region is due to an increase in the frequency of “model” defects (r=0.69, p<0.05), which have a significant hereditary component. It was found that in the urban Kherson population, the relatively high frequency of postnatal violations testifies to the weakening of the “sifting” effect of natural selection. On the contrary, selection in rural populations eliminates most of the non-viable embryos in the early stages of pregnancy, as evidenced by the relatively high prevalence of involuntary miscarriages. In the long term, it is necessary to establish the correlation between the indices of the incidence of congenital and hereditary pathology in populations and the parameters of their genetic and demographic structure.

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Birth defects monitoring program

Teratology ◽

10.1002/tera.1420480604 ◽

1993 ◽

Vol 48 (6) ◽

pp. 550-550

Keyword(s):

Birth Defects ◽

Monitoring Program

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16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716092115 ◽

2018 ◽

Vol 115 (8) ◽

pp. E1849-E1858 ◽

Cited By ~ 17

Author(s):

Meade Haller ◽

Jason Au ◽

Marisol O’Neill ◽

Dolores J. Lamb

Keyword(s):

Transcription Factor ◽

Birth Defects ◽

Copy Number ◽

Congenital Malformations ◽

Survival Rates ◽

Hek293 Cells ◽

High Morbidity ◽

Cell Cycle Regulators ◽

Human Embryonic Kidney Cells ◽

Normal Bladder

Genitourinary (GU) birth defects are among the most common yet least studied congenital malformations. Congenital anomalies of the kidney and urinary tract (CAKUTs) have high morbidity and mortality rates and account for ∼30% of structural birth defects. Copy number variation (CNV) mapping revealed that 16p11.2 is a hotspot for GU development. The only gene covered collectively by all of the mapped GU-patient CNVs was MYC-associated zinc finger transcription factor (MAZ), and MAZ CNV frequency is enriched in nonsyndromic GU-abnormal patients. Knockdown of MAZ in HEK293 cells results in differential expression of several WNT morphogens required for normal GU development, including Wnt11 and Wnt4. MAZ knockdown also prevents efficient transition into S phase, affects transcription of cell-cycle regulators, and abrogates growth of human embryonic kidney cells. Murine Maz is ubiquitously expressed, and a CRISPR-Cas9 mouse model of Maz deletion results in perinatal lethality with survival rates dependent on Maz copy number. Homozygous loss of Maz results in high penetrance of CAKUTs, and Maz is haploinsufficient for normal bladder development. MAZ, once thought to be a simple housekeeping gene, encodes a dosage-sensitive transcription factor that regulates urogenital development and contributes to both nonsyndromic congenital malformations of the GU tract as well as the 16p11.2 phenotype.

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Lessons Learned from CNV Analysis of Major Birth Defects

International Journal of Molecular Sciences ◽

10.3390/ijms21218247 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8247

Author(s):

Alina Christine Hilger ◽

Gabriel Clemens Dworschak ◽

Heiko Martin Reutter

Keyword(s):

Birth Defects ◽

Copy Number ◽

Congenital Malformations ◽

De Novo ◽

Copy Number Variations ◽

Lessons Learned ◽

Organ System ◽

Molecular Karyotyping ◽

The Past ◽

Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

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