Paternal Origin Research Articles

Methylation patterns within 5′-UTR of DAT1 gene as a function of allelic 3′-UTR variants and their maternal or paternal origin: May these affect the psychopathological phenotypes in children? An explorative study

Psychopathological symptoms such as depression/anxiety vs attention or aggression problems, in children, have been associated to altered expression of the DAT1/SLC6A3 gene. Inheriting specific 9- or 10-repeat VNTR alleles could modify the pattern of methylation in the CpGs islands at the 5′-UTR of the DAT1 gene. Through accurate recruitment at primary schools, we ended up with four subgroups of children: 9/9 and 10/10 homozygous; 9/10 heterozygous born from 9/10 mothers and 10/10 fathers (called heM); 9/10 heterozygous born from 10/10 mothers and 9/10 fathers (called heF). (Epi)genetical changes were found to be in relation to internalizing and externalizing symptoms: compared to other genotypes, our 9/9 children exhibited mainly internalizing symptoms, while 10/10 genotype was previously associated with ADHD severity. We found that 10/10 children bear 5′-UTR motifs showing a CpGs 1-2-3-5 unity with anticorrelated CpG 6, while 9/9 children showed rather a demethylated CpG 1 linked to demethylated CpG 6. We found two different patterns between heMs and heFs: a feature of heM children is in CpGs 1-3 methylated pattern with CpGs 2, 5 and 6 demethylated together, supporting a “split” unitary destiny. Within the heF children, the status for CpGs 3 + 6 remained opposite, yet pattern of (de)methylation was not well defined. The prevailing one between inherited parental alleles may somewhat influence the motif destiny of heterozigous children. Present work aimed to identify novel epigenetic biomarkers, to be exploited as fairly indicators of children's psychopathological vulnerability.

The origin of the Qajar Shah dynasty according to their Y-DNA

The subject of the study was the genealogy of the Qajar dynasty, which ruled Iran in 1795-1925. Documentary sources indicate Gara Piri bey Qajar (XV century – 1513), the first beglyarbek of Karabakh with the center in Ganja (now Azerbaijan) as the earliest ancestor of the dynasty. At the end of the XVI century, the great–grandson of Gar Piri bey was appointed Shah Abbas I beglyarbek of Astrabad (now Gorgan, Iran), from whose descendant - Agha Muhammad Khan Qajar (1741-1797), the shah dynasty began. Agha-Mohammed Khan himself traced his family back to a legendary ancestor named Qajar, the son of Sartak-noyon from the Mongolian Jalai tribe, the mentor of Genghisid Argun Khan (1284-1291). According to other sources, the Qajars are a Turkoman tribe that settled in Transcaucasia during the Mongol period. These data on the early history point to the Qajar dynasty as having originally Central Asian origin. In 2007, a study of the Y-DNA of two modern representatives of different lines of the Qajar dynasty was conducted. Tests have shown that both lines really originate from a recent common paternal ancestor and belong to haplogroup J1-M267, widespread in the Middle East. However, apart from the genetic confirmation of the common paternal origin of these two lines and the declaration of the marginality of the ancestral legend, there is virtually no analysis in the work that gives a definitive answer to the question of the origin of the dynasty itself. In the development of this work, a more in-depth study of Y-DNA by new generation sequencing methods was carried out. The paternal origin of the Qajar dynasty from the indigenous population of the northern regions of Azerbaijan has been revealed.

Tierra Del Fuego: What Is Left from the Precolonial Male Lineages?

Similar to other South American regions, Tierra del Fuego has an admixed population characterized by distinct ancestors: Native Americans who first occupied the continent, European settlers who arrived from the late 15th century onwards, and Sub-Saharan Africans who were brought to the Americas for slave labor. To disclose the paternal lineages in the current population from Tierra del Fuego, 196 unrelated males were genotyped for 23 Y-STRs and 52 Y-SNPs. Haplotype and haplogroup diversities were high, indicating the absence of strong founder or drift events. A high frequency of Eurasian haplogroups was detected (94.4%), followed by Native American (5.1%) and African (0.5%) ones. The haplogroup R was the most abundant (48.5%), with the sub-haplogroup R-S116* taking up a quarter of the total dataset. Comparative analyses with other Latin American populations showed similarities with other admixed populations from Argentina. Regarding Eurasian populations, Tierra del Fuego presented similarities with Italian and Iberian populations. In an in-depth analysis of the haplogroup R-M269 and its subtypes, Tierra del Fuego displayed a close proximity to the Iberian Peninsula. The results from this study are in line with the historical records and reflect the severe demographic change led mainly by male newcomers with paternal European origin.

Ultrasonography screening in children and adolescents who have one parent with familial non-medullary thyroid carcinoma.

To evaluate ultrasonography (US) screening for thyroid cancer in children and adolescents who have one parent with familial non-medullary thyroid carcinoma (FNMTC) unrelated to known genetic syndromes. In this prospective study, we selected 72 children and adolescents (age ≤18 years) without a palpable thyroid nodule or history of radiation exposure, but who have one parent diagnosed with FNMTC (i.e. at least one other affected first-degree relative). The children and adolescents were evaluated by US during initial assessment and after 5 years. Initial US revealed pure cysts in five participants and nodules in seven, which were ≥5 mm in five. These patients were submitted to fine needle aspiration, which revealed benign cytology in four and a follicular lesion of undetermined significance in one. Fine needle aspiration was repeated in the last case and in one case with benign cytology but suspicious US. The second cytology was benign in both cases. After 5 years, another two participants with initially normal US had nodules <5 mm in the absence of suspicious findings. The frequency of lesions detected by US was not associated with participant sex or age, number of relatives with thyroid cancer (2 or 3), maternal or paternal origin of tumour, or age of the relatives at diagnosis. The present results suggest that US screening is not necessary in children or adolescents when one parent has a diagnosis of FNMTC (≥2 affected relatives).

Situating the Father: Strengthening Interdisciplinary Collaborations between Sociology, History and the Emerging POHaD Paradigm.

(1) Background: Albeit the main focus remains largely on mothers, in recent years Developmental Origins of Health and Disease (DOHaD) scientists, including epigeneticists, have started to examine how a father’s environment affects disease risk in children and argued that more attention needs to be given to father’s health-related behaviors for their influence on offspring at preconception (i.e., sperm health) as well as paternal lifestyle influences over the first 1000 days. This research ushers in a new paternal origins of health and disease (POHaD) paradigm and is considered a welcome equalization to the overemphasis on maternal influences. Epigeneticists are excited by the possibilities of the POHaD paradigm but are also cautious about how to interpret data and avoid biased impression of socio-biological reality. (2) Methods: We review sociological and historical literatures on the intersection of gender, food and diet across different social and historical contexts to enrich our understanding of the father; (3) Results: Sociological and historical research on family food practices and diet show that there are no “fathers” in the abstract or vacuum, but they are differently classed, racialized and exist in socially stratified situations where choices may be constrained or unavailable. This confirms that epigeneticists researching POHaD need to be cautious in interpreting paternal and maternal dietary influences on offspring health; (4) Conclusions: We suggest that interdisciplinary approach to this new paradigm, which draws on sociology, history and public health, can help provide the social and historical context for interpreting and critically understanding paternal lifestyles and influences on offspring health.

Effectiveness of rearing of replacement heifers from Holstein sires

A change in the genotype of dairy cattle (when increase in the blood portion of Holstein breed) leads to the fact that it is necessary to develop new requirements for the rearing of replacement young animals. The purpose of the work was to analyze the eff ectiveness of rearing of replacement heifers from different Holstein sires. It was found as a result of the conducted studies that replacement heifers grew approximately the same in terms of growth periods and by the age of 18 months reached a live weight of over 500 kg. Despite this, it is possible to note certain features of the change in live weight in heifers originating from diff erent sires. The characteristics of the growth indicators of heifers from diff erent breeding sires by growth periods indicate that there is a signifi cant diff erence between groups aged 6 months in favor of heifers-daughters of sires Renigade and Maximus (p ≤ 0,01) and 12 months in favor of heifers-daughters of sire Maximus (p ≤ 0,01) compared with herdmates received from the sire Thunderlight. A regular, rhythmic change in the gains of the live weight of young animals by growth periods was noted. A positive correlation was revealed between the live weight at the age of 6 months and the live weight at 10 and 12 months, the average positive correlation between the live weight at 6 months and the live weight at 18 months was obtained. Positive high and average correlation coeffi cients were also established between the live weight at the age of heifers 10–12 months and the live weight at 12 and 18 months. Using the results obtained by analyzing the dynamics of live weight and the growth rate of replacement heifers from diff erent breeding sires and using the correlation coeffi cients between the indicators of live weight for the periods of evaluation of the growth of replacement heifers, it is possible to predict with a high degree of probability the intensity of growth of young animals, starting from the age of 6 months. The rearing of replacement heifers up to the age of the fi rst insemination, regardless of their paternal origin, is effective at a high level of profi tability 55,6–55,8 %. Further rearing of replacement heifers reduces the level of profi tability, this is clearly seen in the rearing of heifers–daughters of sires Thunderlight and Maximus. Taking into account these factors, it is possible to increase the efficiency of rearing replacement young animals on the farm.

Does Advanced Paternal Age Increase the Rate of Paternally Derived Aneuploidy as Detected by SNP Array?

Objective: Recent studies have investigated the impact of paternal age on the incidence of embryo aneuploidy using young oocyte donors to control for maternal age, with conflicting results observed. This study takes a different approach, looking at the parental source of embryo aneuploidy as detected by SNP array. The aim was to determine whether the incidence and type of paternal-origin aneuploidy would increase with advancing paternal age. Design: A retrospective study of PGT outcomes from 1541 embryos with trio SNP array linkage-based testing from 2012-2020 across three paternal age groups: &lt;35yrs (n=410), 35-40yrs (n=789) and &gt;40yrs (n=315). The primary outcome was frequency of paternally derived aneuploidy in each age bracket. The secondary endpoint was comparison of the complex abnormality rate and the rates of specific trisomies and monosomies of paternal origin. Results: There was no association between advancing paternal age and prevalence of paternal-origin aneuploidy (&lt;35yrs: 17.8%, 35–40yrs: 16.2%; &gt;40yrs: 17.1%). Moreover, no differences were found between age cohorts in the occurrence of paternal-origin trisomy and paternal-origin monosomy. However, the rate of paternally derived complex abnormal embryos appeared increased with advancing paternal age (&lt;35yrs: 2.9%; 35-40yrs: 3.8%; &gt;40yrs: 4.4%) but did not reach statistical significance. Analysis of specific chromosomes showed the &gt;40yrs cohort had a marked increase in rates of trisomy 4 (2.22% vs. 1.22% &lt;35yrs; 0.63% 35–40yrs), trisomy 10 (0.95% vs. 0.49% &lt;35yrs; 0.38% 35-40yrs), trisomy 12 (1.27% vs. 0.49% &lt;35yrs; 0.51% 35-40yrs) and trisomy 19 (1.59% vs. 0.73% &lt;35yrs; 0.76% 35-40yrs). Unlike previously reports, no clear difference was observed in the rate of trisomy 21 with advancing paternal age. Conclusion: We conclude that there is no association between paternal age and the overall rate of paternal-origin aneuploidy. However, our findings suggest a possible effect of advanced paternal age (&gt;40yrs) on the rate of paternally derived complex abnormalities, as well as increased rate of specific paternal-origin trisomies (4, 10, 12, 19).

RMplex reveals population differences in RM Y-STR mutation rates and provides improved father-son differentiation in Japanese

Rapidly mutating Y chromosomal short tandem repeat markers (RM Y-STRs) –characterized by at least one mutation per 100 generations– are suitable for differentiating both related and unrelated males. The recently introduced multiplex method RMplex allows for the efficient analysis of 30 Y-STRs with increased mutation rates, including all 26 currently known RM Y-STRs. While currently available RM Y-STR mutation rates were established mostly from European individuals, here we applied RMplex to DNA samples of 178 genetically confirmed father-son pairs from East Asia. For several Y-STRs, we found significantly higher mutation rates in Japanese compared to previous estimates. The consequent father-son differentiation rate based on RMplex was significantly higher (52%) in Japanese than previously reported for Europeans (42%), and much higher than with Yfiler Plus in both sample sets (14% and 13%, respectively). Further analysis suggests that the higher mutation and relative differentiation rates in Japanese can in part be explained by on average longer Y-STR alleles relative to Europeans. Moreover, we show that the most striking difference, which was found in DYS712, could be linked to a Y-SNP haplogroup (O1b2-P49) that is common in Japanese and rare in other populations. We encourage the forensic Y-STR community to generate more RMplex data from more population samples of sufficiently large sample size in combination with Y-SNP data to further investigate population effects on mutation and relative differentiation rates. Until more RMplex data from more populations become available, caution shall be placed when applying RM Y-STR mutation rate estimates established in one population, such as Europeans, to forensic casework involving male suspects of paternal origin from other populations, such as non-Europeans.

Distribution and transmission of copy number variations of uncertain significance in 105 trios.

BackgroundThe distribution and genetic characteristics of copy number variations (CNVs) remain unclear. Here, we investigated the distribution and transmission of CNVs of uncertain significance in fetuses.MethodsLow‐coverage massively parallels CNV sequencing of 105 families (parents and their fetuses) was performed to identify fetal CNVs of uncertain significance.ResultsIn the 105 fetuses, 176 CNVs of uncertain significance were detected, and the average number of CNVs carried by fetuses was 1.68 ± 0.80. Among the CNVs carried by the fetuses, 79.8% were inherited (~90.0% of the fetuses) and 20.2% were new mutations (~30.0% of the fetuses). We found that 58.9% CNVs were of maternal origin and 41.1% were of paternal origin. Among the CNV subtypes, de novo CNV distribution was significantly different from inherited CNV distribution. There was no difference in the distribution of maternal and paternal CNV subtypes in the fetuses. The proportion of microdeletions (36.7%) and microduplications (63.3%) was similar in the fetuses and parents. Furthermore, we found that when parents carried more CNVs of uncertain significance, the chance of passing them on to their offspring decreased.ConclusionThis study deepens our understanding of the genetic mechanisms associated with CNV transmission to assist clinicians in prenatal counseling.

Y-STR Kits and Y-STR Diversity in the South African Population

The South African population consists of four ethnic groups, i.e., Blacks, Coloreds, Indians, and Whites, and is considered the most diverse conglomeration of humans. In addition to autosomal short tandem repeat (STR) variation, an important tool to study population diversity is Y-chromosome (Y)-STR analysis. Y-STRs aid in forensic investigations and provide essential data about paternal lineage origins. Y-STR kits consisting of an array of stable and rapidly mutating markers offer crucial information on a given population's genetic and haplotype diversity. This review discusses the development of Y-STR kits over the years and highlights some prominent Y-STR studies conducted on the South African population. The earliest Y-STR kit developed was the Y-PLEX™6, with the most recent being the UniQTyper™ Y-10 Multiplex. The South African population studies show varying data, with the “minimal haplotype” having low discrimination capacity among the ethnic groups and the UniQTyper™ Y-10 showing high genetic diversity among the ethnic groups of the country. There is a dearth of Y-STR studies on the South African population. With the advent of new Y-STR kits with increased discriminatory markers, additional studies are required to represent the South African population in the Y-STR databases. Considering the diversity of the South African population, establishment of a local/regional population database would be beneficial. In addition, data on the origins and prevalence of mutations and silent alleles should be obtained from STR datasets generated during kinship investigations (specifically, parentage tests) so that detailed information about the frequencies of mutations, silent alleles, and uniparental disomy in the South African population at Y STR loci can be estimated.

Ancient genomes reveal complex genetic history of an international metropolis at Kublai Khan's Upper Capital (Xanadu)

AbstractObjectivesAs the political, economic, military, and cultural center of the early Yuan Dynasty, Xanadu attracted people from all over the world. It was thriving and prosperous, composed of residents with different customs and religious beliefs from different social strata. Genetic analysis of Xanadu's residents provides a valuable approach for inferring processes of population movement and exchange during the Yuan period.Materials and MethodsNine skeletons from Zhenzishan cemetery, the largest cemetery near Xanadu, were selected for the whole‐genome shotgun sequencing and capture sequencing of the nonrecombining region of the Y chromosome, three of whom were identified as likely being of European descent based on cranio‐facial morphology.ResultsThere were nine mitochondrial DNA (mtDNA) haplotypes (F1a1, D5b1, B4a3, B5a2a1, H6a1a, T2d1, D4o2a, N9a1, and Z4a) and eight Y‐chromosome DNA haplogroups (G/M201, I/M170, J/M304, L/M20, O/M175, Q/M242, R/M207, and T/M184) identified in the nine ancient individuals. Autosomal analysis further subdivided them into four groups (ZZS_EA, ZZS_CA, ZZS_SA, and ZZS_Cau).DiscussionAs the capital of the Yuan Dynasty, Xanadu was a prosperous city with international influence. The nine skeletons from the Zhenzishan cemetery reflect the high genetic diversity of Xanadu's residents, with clear differences in paternal and maternal origins. The maternal lineages of these residents were mainly East Asian with some western Eurasian features, while the paternal lineages were mainly western Eurasian with fewer East Asian features. These results contribute to a better understanding of the Mongolian Empire's impact on the migration and mixture of people across the Eurasian continent.

IGF2R, KCNQ1, PLAGL1, and SNRPN DNA methylation is completed in bovine by the early antral follicle stage.

Imprinted genes are inherited with different DNA methylation patterns depending on the maternal or paternal origin of the allele. In cattle (Bos taurus), abnormal methylation of these genes is linked to the large offspring syndrome, a neonatal overgrowth phenotype analogous to the human Beckwith-Wiedemann syndrome. We hypothesized that in bovine oocytes, some of the methylation patterns on maternally imprinted genes are acquired in the last phase of folliculogenesis. The pyrosequencing analysis of IGF2R, KCNQ1, PLAGL1, and SNRPN imprinted genes showed no clear progression of methylation in oocytes from follicles 1-2 mm (late pre antral/early antral) and up. Instead, these oocytes displayed complete methylation at the imprinted differentially methylated regions (>80%). Other mechanisms related to imprint maintenance should be investigated to explain the hypomethylation at IGF2R, KCNQ1, PLAGL1, and SNRPN maternally imprinted sites observed in some bovine embryos.

Concomitant CNVs in healthy carriers with 7q31.1 microdeletions may suppress intellectual disability and autism spectrum disorders phenotype

IntroductionAbout 66% of chromosomal microdeletions and microduplications associated with pathological conditions are inherited [Smajlagić D. et al., 2021]. The mechanisms of incomplete penetrance and variable expressivity of CNV are not fully understood. The presence of concomitant CNVs in the genome of healthy parents may have a modifying effect.ObjectivesIdentification of additional CNVs in healthy carriers with 7q31.1 microdeletions.MethodsCNVs were revealed by Agilent Technologies 60K microarray and confirmed by qPCR.ResultsWe examined 3 families with inherited 7q31.1 microdeletions affecting only the IMMP2L gene, which is associated with intellectual disability, developmental delay and autism spectrum disorders. Family 1: Proband has intellectual disability, developmental delay, sensorimotor alalia. Microdeletion was inherited from the father, and a healthy sibling is also a carrier of rearrangement. In sibs, additional CNVs were identified: arr[hg19]: 4q31.21(144722583_144939143)×3; 9p12p11.2(43588066_43836428)×3; 16p11.2(32066967_33773163)×1; and 17q21.31(44199517_44577208)×3. Family 2: Proband suffers from development delay, speech disorder and autism. Microdeletion was of paternal origin. The father additionally demonstrated microduplication 16p11.2p11.1(33967926-35204414)×3. Family 3: Proband was diagnosed with development delay and cerebral palsy. The mother is a carrier of a similar 7q31.1 microdeletion; two concomitant CNVs were identified in her karyotype: 9p13.1(39176840_40614884)×3; and 16p11.2p11.1(32833891_35204414)×3. Thus, healthy parents in 3 families have CNV in a common region 16p11.2, which contains the TP53TG3 gene. It is important that TP53TG3 expression is associated with epistatic CNV-CNV interactions [Sun, Kardia 2010].ConclusionsMultiple CNVs in apparently healthy carriers of IMMP2L microdeltions may suppress disease phenotype due to the epistatic CNV-CNV interaction. This study was supported by Russian Science Foundation, grant no. 21-75-00112.DisclosureNo significant relationships.

Distinct Roles of Classical and Lectin Pathways of Complement in Preeclamptic Placentae.

Pre-eclampsia is a pregnancy complication characterized by defective vascular remodeling in maternal decidua responsible for reduced blood flow leading to functional and structural alterations in the placenta. We have investigated the contribution of the complement system to decidual vascular changes and showed that trophoblasts surrounding unremodeled vessels prevalent in preeclamptic decidua fail to express C1q that are clearly detected in cells around remodeled vessels predominant in control placenta. The critical role of C1q is supported by the finding that decidual trophoblasts of female C1qa-/- pregnant mice mated to C1qa+/+ male mice surrounding remodeled vessels express C1q of paternal origin. Unlike C1qa-/- pregnant mice, heterozygous C1qa+/- and wild type pregnant mice share a high percentage of remodeled vessels. C1q was also found in decidual vessels and stroma of normal placentae and the staining was stronger in preeclamptic placentae. Failure to detect placental deposition of C1r and C1s associated with C1q rules out complement activation through the classical pathway. Conversely, the intense staining of decidual endothelial cells and villous trophoblast for ficolin-3, MASP-1 and MASP-2 supports the activation of the lectin pathway that proceeds with the cleavage of C4 and C3 and the assembly of the terminal complex. These data extend to humans our previous findings of complement activation through the lectin pathway in an animal model of pre-eclampsia and provide evidence for an important contribution of C1q in decidual vascular remodeling.

Relationship between paternal factors and embryonic aneuploidy of paternal origin

To determine if there is a relationship between paternal factors and embryonic aneuploidy of paternal origin using preimplantation genetic testing for aneuploidy (PGT-A). Retrospective cohort. Academic. Couples undergoing invitro fertilization with PGT-A. None. To determine if there is an association between paternal age, body mass index (BMI), or semen analysis parameters and paternal aneuploidy. From January 2015-2020, 453 invitro fertilization cycles (1,720 embryos) underwent PGT-A using single nucleotide polymorphism microarrays with parental support bioinformatics. The mean (±SD) was 36.5 (±3.5) years for maternal age, 39.5 (±5.5) years for paternal age, 24.7 (±5.0) kg/m2 for maternal BMI, and 27.6 (±4.3) kg/m2 for paternal BMI. Embryonic aneuploidy of paternal origin was found in 8.4% (144/1,720) embryos. There were 1,533 embryos with a recorded paternal BMI. Rates of embryonic aneuploidy of paternal origin were similar between men across BMI groups: BMI 18-24.9 kg/m2 was 7.2% (referent); BMI 25-29.9 kg/m2 was 8.4% (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.79-1.82); and BMI ≥30 kg/m2 was 9.1% (OR, 1.31; 95% CI, 0.83-2.08). There were 854 embryos from men with a normal and 866 from men with an abnormal semen analysis. No differences were found in the rate of embryonic aneuploidy of paternal origin between men with normal and abnormal sperm concentration, total count, motility, progressive motility, or morphology. No significant difference was seen in rates of aneuploidy between men aged <50 years and those aged ≥50 years (OR, 1.69; 95% CI, 0.96-2.98). No association was found between paternal age, BMI, or semen analysis parameters and paternal aneuploidy.

Effect of Paternal Diet on Spermatogenesis and Offspring Health: Focus on Epigenetics and Interventions with Food Bioactive Compounds.

Infertility is a growing public health problem. Consumption of antioxidant bioactive food compounds (BFCs) that include micronutrients and non-nutrients has been highlighted as a potential strategy to protect against oxidative and inflammatory damage in the male reproductive system induced by obesity, alcohol, and toxicants and, thus, improve spermatogenesis and the fertility parameters. Paternal consumption of such dietary compounds could not only benefit the fathers but their offspring as well. Studies in the new field of paternal origins of health and disease show that paternal malnutrition can alter sperm epigenome, and this can alter fetal development and program an increased risk of metabolic diseases and breast cancer in adulthood. BFCs, such as ascorbic acid, α-tocopherol, polyunsaturated fatty acids, trace elements, carnitines, N-acetylcysteine, and coenzyme Q10, have been shown to improve male gametogenesis, modulate epigenetics of germ cells, and the epigenetic signature of the offspring, restoring offspring metabolic health induced by stressors during early life. This indicates that, from a father’s perspective, preconception is a valuable window of opportunity to start potential nutritional interventions with these BFCs to maximize sperm epigenetic integrity and promote adequate fetal growth and development, thus preventing chronic disease in adulthood.

Clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children

To study the clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children. The medical data of 200 children with epilepsy who underwent a genetic analysis of epilepsy by the whole exon sequencing technology were collected retrospectively, of whom 9 children with epilepsy had 16p11.2 microdeletion. The clinical phenotype and genetic features of the 9 children with 16p11.2 microdeletion were analyzed. The detection rate of 16p11.2 microdeletion was 4.5% (9/200). The 9 children with 16p11.2 microdeletion were 3-10 months old. They experienced focal motor seizures with consciousness disturbance, and some of the seizures developed into generalized tonic-clonic seizures. The interictal electroencephalogram showed focal or multifocal epileptiform discharge, and all 9 children responded well to antiepileptic drugs. The 9 children had a 16p11.2 deletion fragment size of 398-906 kb, and the number of deleted genes was 23-33 which were all pathogenic mutations. The mutation was of maternal origin in 2 children, of paternal origin in 1 child, and de novo in the other children. 16p11.2 microdeletion can be detected in some children with epilepsy. Most of the 16p11.2 microdeletion is de novo mutation and large gene fragment deletion. The onset of 16p11.2 microdeletion-related epilepsy in children is mostly within 1 year of life, and the epilepsy is drug-responsive.

Clinical characteristics and genetics analysis for the ITD of congenital hypothyroidism.

Iodide transport defect (ITD) is one of the principal causes of congenital hypothyroidism (CH) and its primary molecular mechanism is a mutation of the sodium/iodide symporter (NIS) gene. This study aims to analyse the clinical characteristics and genetic mutations of ITD. The participants were a pair of siblings diagnosed with congenital hypothyroidism. Inductively coupled plasma mass spectrometry was used to determine the concentration of salivary iodine and serum iodine and to calculate their ratio. At the same time, next-generation sequencing (NGS) was applied to detect all exons of congenital hypothyroidism-related genes. All suspicious variants were further validated in the patients and their parents by PCR and Sanger sequencing. Both patients were conclusively diagnosed with thyroid iodine transport defect (ITD). NGS identified two variants of the NIS gene in the siblings: c.1021G>A (p.Gly341Arg) with paternal origin and c.1330-2A>C with maternal origin. Both of these variants have not been reported to date. They are predicted to be pathogenic based on these clinical symptoms and comprehensive software analysis. This is the first reported family study of congenital hypothyroidism with SLC5A5 mutation in China. Next-generation sequencing technology is an effective means of studying the genetics of congenital hypothyroidism. The therapeutic effect of potassium iodide needs to be further evaluated.

Sensitive screening of single nucleotide polymorphisms in cell free DNA for diagnosis of gestational tumours

Tumours expressing human chorionic gonadotropin (hCG), the majority of which are difficult to biopsy due to their vascularity, have disparate prognoses depending on their origin. As optimal management relies on accurate diagnosis, we aimed to develop a sensitive cell free DNA (cfDNA) assay to non-invasively distinguish between cases of gestational and non-gestational origin. Deep error-corrected Illumina sequencing of 195 common single nucleotide polymorphisms (SNPs) in cfDNA and matched genomic DNA from 36 patients with hCG-secreting tumours (serum hCG 5 to 3,042,881 IU/L) and 7 controls with normal hCG levels (≤4 IU/L) was performed. cfDNA from confirmed gestational tumours with hCG levels ranging from 1497 to 700,855 IU/L had multiple (n ≥ 12) ‘non-host’ alleles (i.e. alleles of paternal origin). In such cases the non-host fraction of cfDNA ranged from 0.3 to 40.4% and correlated with serum hCG levels. At lower hCG levels the ability to detect non-host cfDNA was variable, with the detection limit dependent on the type of causative pregnancy. Patients with non-gestational tumours were identifiable by the absence of non-host cfDNA, with copy number alterations detectable in the majority of cases. Following validation in a larger cohort, our sensitive assay will enable clinicians to better inform patients, for whom biopsy is inappropriate, of their prognosis and provide optimum management.

CLO22-073: Familial Nevoid Basal Cell Carcinoma Syndrome (NBCCS) Associated to Novel PTCH1 Mutation c.1067 + 2T&gt;C of Paternal Origin in Somatic Mosaicism With Marked Phenotypic Variation in the Children

"CLO22-073: Familial Nevoid Basal Cell Carcinoma Syndrome (NBCCS) Associated to Novel PTCH1 Mutation c.1067 + 2T>C of Paternal Origin in Somatic Mosaicism With Marked Phenotypic Variation in the Children" published on 31 Mar 2022 by National Comprehensive Cancer Network.