Paternal Side Research Articles

12386 Unilateral Spontaneous Adrenal Hemorrhage In Pregnancy

Abstract Disclosure: A. Gondhi: None. M. Campana: None. M. Riofrio: None. J. Fazendin: None. D. Vodopivec: None. Unilateral Spontaneous Adrenal Hemorrhage In Pregnancy Introduction: Spontaneous adrenal hemorrhage (SAH) in pregnancy is a rare and under recognized entity with an incidence of 0.14% - 1.1%, mostly unilateral. We present a case of unilateral SAH managed with adrenalectomy during pregnancy. Case presentation: A 24-year-old 14-weeks pregnant woman was referred for right flank pain and nausea due to right adrenal lesion. Medical history significant for 4 first trimester miscarriages and family history of Breast cancer and Uterine cancer in mother, Pancreatic cancer in multiple family members on paternal side. She was hemodynamically stable. Abdominal-US showed right adrenal lesion. Non-contrast MRI abdomen showed a large collection in the right adrenal gland measuring 9.6cm x 9cm. Ability to assess for underlying lesion challenging given the amount of blood products and lack of IV contrast. Laboratory analysis showed an appropriately suppressed cortisol with 1 mg overnight dexamethasone suppression test (cortisol 1.3 mcg/dl, N<1.8 mcg/d Dexamethasone level 332 ng/dl, N<180-550 ng/dl), normal DHEA-S (135 mcg/dl, N=18-391mcg/dl), non-suppressed ACTH (18 pg/ml, N 7.2-63 pg/ml), normal aldosterone (8.1 ng/dl, N=3-39.2 ng/dl) with a non-suppressed renin (17.8 pg/ml, N=4.2-52.2 pg/ml), normal fractionated plasma metanephrines (Free metanephrines <0.2 nMol/L, N<0.0.5nMol/L Free normetaphrines <0.2 nMol/L, N<0.9nMol/L), negative Antiphopholipid antibody testing (Beta 2 Glycoprotein I IgM <2 U/ml, N<20U/ml, Beta 2 Glycoprotein I IgG 2.2 U/ml, N<20U/ml). The patient underwent a laparoscopic converted to open right adrenalectomy. Pathology showed a 9.6cm adrenal gland with organizing hematoma, vascular congestion, and hemorrhage. It also showed periadrenal adipose tissue with atypia, MDM2 gene amplification by FISH negative – ruling out liposarcoma. Post-operatively, her symptoms resolved without complications to the pregnancy. Differentials for adrenal hemorrhage in this pregnant patient include: 1) underlying adrenal tumor (most commonly pheochromocytoma), 2) coagulopathy (e.g. antiphospholipid syndrome), and 3) pregnancy-related adrenal hemorrhage (rare, mostly unilateral due to increased vascular flow to the adrenal gland and the hypercoagulability). After evaluating the adrenal functionality, APLAS and assessing the malignant potential with imaging studies; conservative management is appropriate in stable patients. Our patient underwent surgery due to recurrent intractable pain, and uncertainty regarding malignant potential of the adrenal mass given history of multiple cancers in the family. Conclusion: Our case highlights that when indicated, adrenalectomy in the II trimester is a safe and effective option in pregnancy. Individualized treatment should be chosen for each patient following shared decision-making. Presentation: 6/1/2024

Monogenic obesity in a familial cluster: insights into laurence-moon-bardet-biedl syndrome and leptin deficiency associated with genetic variants in BBS12 and LEPR genes

Monogenic obesity is a rare but clinically significant condition characterized by excessive weight gain due to genetic mutations that affect appetite regulation and energy balance. This case series explores the clinical presentation and genetic underpinnings of monogenic obesity in a familial cluster, focusing on Laurence-Moon-Bardet-Biedl Syndrome (LMBBS) and leptin deficiency associated with genetic variants in the BBS1 and LEPR genes. The index patient, an 11-year-old female, presented with progressive weight gain since infancy, accompanied by acanthosis nigricans on the neck and axillary region. Genetic testing revealed mutations in both the BBS1 and LEPR genes, confirming a monogenic etiology of obesity. Remarkably, her two siblings and a cousin from the paternal side exhibited similar clinical profiles and shared the same genetic variants. This report shows the significance of genetic testing in diagnosing monogenic obesity disorders and highlights the familial clustering observed in such cases. The findings emphasize the need for heightened awareness and consideration of genetic factors in the evaluation of obesity, particularly in pediatric patients with a family history suggestive of monogenic obesity.

Colorectal cancer with a germline BRCA1 variant inherited paternally: a case report.

BRCA genes have well-known associations with breast and ovarian cancers. However, variations in the BRCA gene, especially germline variations, have also been reported in colorectal cancer (CRC). We present the case of a rectal cancer with a germline BRCA1 variation inherited from the paternal side. A 39-year-old male was admitted with rectal cancer. The patient underwent surgical resection and the pathologic diagnosis was adenocarcinoma. Next-generation sequencing was performed and a BRCA1 variant was detected. Reviewing the public database and considering the young age of the patient, the variant was suggested to be germline. The patient's father had had prostate cancer and next-generation sequencing testing revealed an identical BRCA1 variant. In the BRCA cancer group, there is relatively little attention paid to male cancers. The accumulation of male CRC cases linked to BRCA variations may help clarify the potential pathological relationship between the two.

Parent of origin genetic effects on milk production traits in a population of Iranian Holstein cows.

The aim was to estimate the relative contribution of imprinting effects from both paternal and maternal sides to phenotypic variation in milk production traits including 305 days milk yield (MY), average daily milk production (ADM), fat percentage (F%), protein percentage (P%), 305 days fat yield (FY), 305 days protein yield (PY), ratio of fat percentage to protein percentage (F:P) and somatic cell score (SCS) in Iranian Holstein cows. To do this, each trait was analysed with a series of four animal models, which were identical for fixed and additive genetic effects but differed for combinations of paternal and maternal imprinting effects. The log-likelihood ratio test (LRT) and Akaike's information criteria (AIC) were used to select the best model for each trait. Correlations between traits due to additive and imprinting effects were estimated by bivariate analyses. For all traits studied, fitting the imprinting effect led to a better data fit. Also, it resulted in a noticeable decrease in additive genetic variance from 8% (SCS) to 28% (F:P). A significant maternal imprinting effect was detected on all traits studied. Estimates of maternal imprinting heritability ( ) were 0.07 ± 0.02, 0.04 ± 0.01, 0.06 ± 0.01, 0.05 ± 0.01, 0.5 ± 0.01, 0.09 ± 0.02, 0.07 ± 0.02 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. For F:P, in addition to the maternal imprinting effect, a significant paternal imprinting component was also detected with a 7% contribution to phenotypic variance of F:P. Estimates of direct heritability ( ) were 0.29 ± 0.02, 0.17 ± 0.01, 0.22 ± 0.02, 0.11 ± 0.01, 0.18 ± 0.02, 0.22 ± 0.02, 0.15 ± 0.04 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. Maternal imprinting correlations (rmi) were in a wide range between -0.75 ± 0.15 (P%-SCS) and 0.95 ± 0.11 (MY-ADM). Additive genetic correlations (ra) ranged between -0.54 ± 0.05 (MY-P%) and 0.99 ± 0.01 (MY-ADM) and phenotypic correlations (rp) ranged from -0.30 ± 0.01 (MY-F%) to 0.93 ± 0.01 (MY-ADM). The Spearman's correlation between additive breeding values including and excluding imprinting effects deviated from unity especially for top-ranked animals implying re-ranking of top animals following the inclusion of imprinting effects in the model. Since including imprinting effects in the model resulted in better data fit and re-ranking of top animals, including these effects in the genetic evaluation models for milk production traits was recommended.

Male-biased recombination at chromosome ends in a songbird revealed by precisely mapping crossover positions.

Recombination plays a crucial role in evolution by generating novel haplotypes and disrupting linkage between genes, thereby enhancing the efficiency of selection. Here, we analyze the genomes of 12 great reed warblers (Acrocephalus arundinaceus) in a 3-generation pedigree to identify precise crossover positions along the chromosomes. We located more than 200 crossovers and found that these were highly concentrated toward the telomeric ends of the chromosomes. Apart from this major pattern in the recombination landscape, we found significantly higher frequencies of crossovers in genic compared with intergenic regions, and in exons compared with introns. Moreover, while the number of recombination events was similar between the sexes, the crossovers were located significantly closer to the ends of paternal compared with maternal chromosomes. In conclusion, our study of the great reed warbler revealed substantial variation in crossover frequencies within chromosomes, with a distinct bias toward the sub-telomeric regions, particularly on the paternal side. These findings emphasize the importance of thoroughly screening the entire length of chromosomes to characterize the recombination landscape and uncover potential sex-biases in recombination.

“Whatever is bad goes back to the woman”: The gendered blame game of sickle cell disease in Malawi and Uganda

Mothers are commonly blamed for the ill-health of their children, and this is well documented in research. However, few studies have considered gendered patterns of blame for hereditary conditions caused by mutations from both parents through dual, shared genetic inheritance. This paper explores the ‘gendering’ of blame in the context of an inherited blood disorder known as sickle cell disease. The findings are drawn from 18 focus group discussions with 117 caregivers of children with sickle cell disease in Malawi and Uganda. Although one mutation from each parent is required for the disease to develop, low awareness about their status as healthy carriers of a sickle cell trait complicated the caregivers' recognition and acceptance of their genetic link to the child's condition. This study demonstrates how fathers and other members of the paternal side of the child's family would deflect blame from their own lineage by directing sole ‘genetic responsibility’ for the child's disease towards mothers. We discuss the implications of gendered blame on household dynamics and healthcare-seeking for children with sickle cell disease in this setting.

An observational analysis on the influence of parental allergic rhinitis, asthma and smoking on exhaled nitric oxide in offspring

BackgroundParental allergic diseases and smoking influence respiratory disease in the offspring but it is not known whether they influence fractional exhaled nitric oxide (FeNO) in the offspring. We investigated whether parental allergic diseases, parental smoking and FeNO levels in parents were associated with FeNO levels in their offspring. MethodsWe studied 609 offspring aged 16–47 years from the Respiratory Health in Northern Europe, Spain and Australia generation (RHINESSA) study with parental information from the Respiratory Health in Northern Europe (RHINE) III study and the European Community Respiratory Health Survey (ECRHS) III. Linear regression models were used to assess the association between offspring FeNO and parental FeNO, allergic rhinitis, asthma and smoking, while adjusting for potential confounding factors. ResultsParental allergic rhinitis was significantly associated with higher FeNO in the offspring, both on the paternal and maternal side (percent change: 20.3 % [95%CI 5.0–37.7], p = 0.008, and 13.8 % [0.4–28.9], p = 0.043, respectively). Parental allergic rhinitis with asthma in any parent was also significantly associated with higher offspring FeNO (16.2 % [0.9–33.9], p = 0.037). However, parental asthma alone and smoking were not associated with offspring FeNO. Parental FeNO was not associated with offspring FeNO after full adjustments for offspring and parental factors. ConclusionsParental allergic rhinitis but not parental asthma was associated with higher levels of FeNO in offspring. These findings suggest that parental allergic rhinitis status should be considered when interpreting FeNO levels in offspring beyond childhood.

Familial cancer with BRCA2 and other germline variants: A case report

High-resolution genomic studies can help understanding the predisposition to cancer by identifying constitutional genetic variants of differential penetrance and pathogenicity in a family. We present a case report of whole exome analysis in a case (62/Female) with a history of pancreatic, intestinal, and prostate cancers in the paternal side and her unaffected son from Gujarat, India. Proband showed germline alterations in BRCA2 and NOS3 genes and in NTHL1 gene in her son. BRCA2 c.8954-3C > G has conflicting interpretations being characterized as likely pathogenic and variant of unknown significance (VUS) in 2018 and 2021, while our findings in 2022 classifies it as likely pathogenic. Novel germline genetic variants NOS3 c.1246_1255del (p. Ile417Thrfster9) and NTHL1 c.374dup (p. Val127GlyfsTer43) have been classified as VUS. In-silico analysis of the BRCA2 c.8954-3C > G indicates the location of the genetic variant at the splice site. Proband and her son show co-segregation of 9 constitutional genetic variants; 8 are likely benign and one is benign according to ClinVar. Identification of germline variants and studies on functional evidence will facilitate curated genetic counselling for the family and focussed risk-reduction strategies.

Abstract PO1-20-07: Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene?

Abstract Introduction: Mutations in the valosin-containing protein (VCP, also known as p97) gene are associated with autosomal dominant inclusion-body myopathy with early-onset Paget disease and frontotemporal dementia. VCP is an ATPase that subserves a variety of cellular functions, prominently, organelle biogenesis and ubiquitin-dependent protein degradation. Recently, VCP has also been shown to physically interact with BRCA1 and is postulated to orchestrate the response to DNA double-strand breaks, a critical molecular prelude to homologous recombination DNA repair. Moreover, VCP is also involved in the removal of trapped poly [ADP-ribose] polymerase 1 (PARP1) from chromatin and may play a key role in the response of tumor cells to PARP inhibitors. Whether VCP acts as a breast cancer predisposition gene is currently unknown. These observations raise speculation as to whether pathologic variation in VCP may predispose to breast cancer. Case Description: A 45-year-old female presented with early-age, locally advanced invasive ductal carcinoma, grade 2, ER < 1%, PR 10%, HER2 IHC 3+, FISH ratio 5.4. The patient completed 6 cycles of neoadjuvant PTH and was surgically downstaged to ypT1bN1a at the time of her left mastectomy. She declined adjuvant radiation. She received 1 dose of trastuzumab emtansine which was discontinued due to intolerance and transitioned to complete 1 year of adjuvant trastuzumab and pertuzumab. Her medical history is significant for inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia, which was diagnosed at age 36 after presenting with proximal muscle weakness. Bone scan was consistent with Paget’s disease and neurocognitive testing did not identify any abnormalities. Diagnosis was confirmed via whole genome germline sequencing which identified a pathogenic variant in VCP [c.463C >G (p.Arg155Gly)]. Germline resequencing of 155 known cancer predisposition genes did not identify any pathogenic variants. Whole exome genomic analysis of the patient’s breast cancer revealed an elevated homologous recombination score ( > 42), consistent with molecularly important role of VCP in homologous recombination breast cancer DNA repair. The patient’s family history is significant for muscular dystrophy in multiple family members on her paternal side, each of whom was deceased prior to age 60. Her paternal half-sister has both inclusion body myopathy and breast cancer, and her paternal cousin was diagnosed with breast cancer at age 46 (unknown genetic testing for each). No history of cancer on her maternal side. Discussion: This case raises the intriguing question of whether the VCP gene represents a heretofore unrecognized breast cancer predisposition gene. Further investigation into the role of VCP in tumorigenesis is warranted, and additional population studies are necessary to confirm VCP’s role in breast cancer predisposition. Given that cancers with homologous recombination deficiencies benefit from PARP inhibitors and VCP is involved in the function of the PARP1 protein, patients with mutations in the VCP gene may benefit from PARP inhibition. Citation Format: Alexis LeVee, Duveen Sturgeon, Joanne Mortimer, Kevin McDonnell. Valosin-containing protein (VCP)/p97: A novel breast cancer susceptibility gene? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-07.

Repeated pregnancy losses with multiple aneuploidies and major genomic imbalance: A case report

Rationale: If one of the partners is having balanced autosomal translocation, it is usually observed that the offspring inherit either normal chromosomes, balanced translocation identical to one of the parent or unbalanced chromosomal rearrangements of the same parental chromosome having translocation. Concern: A unique case presented with history of 8 miscarriages for genetic counseling. The last abortus material evaluation showed monosomy of chromosome X (Turner syndrome) in all the analyzed cells. There was a history of infertility and also repeated second trimester abortions on the paternal side. On the maternal side, there was a history of intellectual disability. Diagnose: History of repeated abnormal pregnancy outcomes. Wife’s karyotype is normal; however, husband shows translocation between chromosome 4 and 22. Intervention: Peripheral blood sample around 3 mL was collected for karyotype. Embryo biopsy was done and DNA was extracted and processed for whole exome sequencing. Outcomes: Wife’s karyotype is normal and husband has translocation between chromosome 4 and 22. Surprisingly, the entire pregnancy outcome including embryo screening has different, complete or partial aneuploidies of chromosomes other than chromosome 4 and 22. Main lesson: Though the translocation in one of the parent is balanced, we have to think beyond traditional ways for evaluating a couple with repeated pregnancy loss as we cannot predict the errors at cell division. Option of in vitro fertilization and preimplantation genetic diagnosis in couples having balanced translocations should be discussed so that early intervention can prevent the agony of pregnancy loss.

A POSITIVE FAMILY HISTORY, PARTICULARLY IN THE MOTHER, IS AN IMPORTANT DETERMINANT FOR THE DEVELOPMENT OF ARTERIAL HYPERTENSION

Objective: A positive family history is one of the non-modifiable risk factors directly linked to arterial hypertension (AH). This study aimed to show the influence of a positive family history of AH on the incidence of AH in the studied population. Design and method: A total of 1784 participants (a random sample of the general adult population in Croatia included in the ’Epidemiology of Hypertension in Croatia -2’ project) were examined. Data were systematically collected through a structured questionnaire. Results: Analysis showed a statistically significant difference in having a positive family history of AH in at least one parent between those having AH and the normotensive group (59.2% vs. 51.6%; p=0.002). Furthermore, 14.5% of subjects with AH and 9.4% of normotensive subjects reported at least one of the grandmothers with a history of AH (p=0.001). A significant correlation was observed for individuals reporting a positive history of AH in their paternal grandmother (p=0.004) and maternal grandfather (p=0.009), reported by 8.8% and 6.4% of subjects with AH, respectively, as opposed to 5.5% and 4.5% of the normotensive subjects. The most significant difference was found for a positive family history of AH in the mother, reported by 46.5% of subjects with AH and 38.5% of normotensive subjects (p<0.001). Regression analysis indicated a statistically significant association between a positive family history of AH in the mother and an increased odds ratio for developing AH (OR 1.36 95% CI 1.11-1.66, p=0.003). Conversely, a positive family history on either the paternal or maternal side, at least one of the grandfathers, father, and paternal grandfather failed to exhibit a significant correlation with the occurrence of AH. Conclusions: Our study affirmed the importance of family history for arterial hypertension, which should be an elementary part of taking medical history. Subjects who had mothers with arterial hypertension were at higher risk of having AH themselves which is in line with the previous notion that the mother's hypertensive status is more important than the father's.

Fish Oil Improves Offspring Metabolic Health of Paternal Obese Mice by Targeting Adipose Tissue.

Obesity is a fast-growing epidemic affecting more than 40% of the US population and leads to co-morbidities such as type 2 diabetes and cancer. More importantly, there is a rapid increase in childhood obesity associated with obesity in parents. Further, offspring are encoded with approximately half of their genetic information from the paternal side. Obesity in fathers at the preconceptional period likely influences the intergenerational development of obesity. This study focuses on the role of fish oil supplementation as a non-pharmacological intervention in fathers and its impact on childhood obesity using animal models. Male mice were fed a low-fat diet or high-fat diet with or without fish oil for 10 weeks and mated with female mice on a chow diet. Offspring were then continued on a chow diet until 8 or 16 weeks. In vivo insulin tolerance was tested to assess the metabolic health of offspring. Further, adipose tissue was harvested upon sacrifice, and genetic markers of inflammation and lipid metabolism in the tissue were analyzed. Offspring of males supplemented with fish oil showed lower body weight, improved insulin tolerance, and altered inflammatory markers. Markers of fatty acid oxidation were higher, while markers of fatty acid synthesis were lower in offspring of fathers fed fish oil. This supports fish oil as an accessible intervention to improve offspring metabolic health.

Family in Medieval Society: A Bioarchaeological Perspective

One of the periods with the greatest social, cultural, and religious changes was, without a doubt, the European medieval period. The concept of “Family” was one of the fields that gradually evolved, from individuals who shared the same biological lineage, to members of the same “House”. One of the ways to study the concept of “Family” in ancient periods is through a bioarchaeological perspective, where both anthropology and genetics have proven to be essential disciplines for studying “Families”. Through burial rituals, observing whether the graves were single or multiple, as is carried out in the study of human remains, we discuss the profound contribution of anthropology to the “Family” investigation, through mobility studies, the investigation of biological sex, observing certain congenital anomalies or, even, the study of certain ancient infectious diseases. Concerning genetics, the study of bones or teeth allows us to determine whether individuals were from the same close family or if they belonged to the same lineage through the maternal and paternal sides, being one of the only scientific ways of proposing social relationships between individuals, such as that created through adoption.

Shoulder dystocia by severity in families: A nationwide population study.

Previous studies have established a history of shoulder dystocia as an important risk factor for shoulder dystocia, but studies on shoulder dystocia by severity are scarce. It is unknown if shoulder dystocia tends to be passed on between generations. We aimed to assess the recurrence risk of shoulder dystocia by severity in the same woman and between generations on both the maternal and paternal side. We also assessed the likelihood of a second delivery and planned cesarean section after shoulder dystocia. This was a population-based cohort study, using data from the Medical Birth Registry of Norway. To study recurrence in the same mother, we identified 1 091 067 pairs of first and second, second and third, and third and fourth births in the same mother. To study intergenerational recurrence, we identified an individual both as a newborn and as a mother or father in 824 323 mother-offspring pairs and 614 663 father-offspring pairs. We used Bayesian log-binomial multilevel regression to calculate relative risks (RR) with 95% credible intervals. In subsequent deliveries in the same woman the unadjusted RR of recurrence was 7.05 (95% credible interval 6.39-7.79) and 2.99 (2.71-3.31) after adjusting for possible confounders, including current birthweight. The RRs were higher with severe shoulder dystocia as exposure or outcome. With severe shoulder dystocia as both exposure and outcome, unadjusted and adjusted RR was 20.42 (14.25-29.26) and 6.29 (4.41-8.99), respectively. Women with severe and mild shoulder dystocia and those without had subsequent delivery rates of 71.1, 68.9 and 69.0%, respectively. However, the rates of planned cesarean section in subsequent deliveries for those without shoulder dystocia, mild and severe were 1.3, 5.2 and 16.0%, respectively. On the maternal side the unadjusted inter-generational RR of recurrence was 2.82 (2.25-3.54) and 1.41 (1.05-1.90) on the paternal side. Corresponding adjusted RRs were 1.90 (1.51-2.40) and 1.19 (0.88-1.61), respectively. We found a strong recurrence risk of shoulder dystocia, especially severe, in subsequent deliveries in the same woman. The inter-generational recurrence risk was higher on the maternal than paternal side. Women with a history of shoulder dystocia had more often planned cesarean section.

Haploid embryos and embryonic stem cells to produce offspring with predetermined parental genomes in cattle.

Selection strategies are performed post-fertilization when the random combination of paternal and maternal genomes has already occurred. It would be greatly advantageous to eliminate meiotic uncertainty by selecting genetically superior gametes before fertilization. To achieve this goal, haploid embryonic cells and embryonic stem cell lineages could be derived, genotyped, and used to substitute gametes. On the paternal side, androgenetic development can be achieved by removing the maternal chromosomes from the oocyte before or after fertilization. We have shown that once developed into an embryo, haploid cells can be removed for genotyping and, if carrying the selected genome, be used to replace sperm at fertilization. A similar strategy can be used on the maternal side by activating the oocyte parthenogenetically and using some embryonic cells for genotyping while the remaining are used to produce diploid embryos by fertilization. Placed together, both androgenetic and parthenogenetic haploid cells that have been genotyped to identify optimal genomes can be used to produce offspring with predetermined genomes. Successes and problems in developing such a breeding platform to achieve this goal are described and discussed below.

Germline Variant in ZCCHC8 Is Associated with Pulmonary Fibrosis, Bone Marrow Failure, Liver Inflammation, Early Grey Hair and Short Telomer Length

Introduction Telomere biology disorders (TBD) encompass rare genetic conditions that affect telomere function. TBD is associated with a wide range of symptoms, including hematologic, dermatologic, pulmonary, hepatic manifestations. Research is continuously identifying novel variants and genes causative of TBD. In a recent study, Gable et al. (2019) detected a germline missense variant in ZCCHC8 (NM_017612.5:c.557C>T; p.(Pro186Leu)) in a single family with pulmonary fibrosis. This ZCCHC8 variant was associated with short telomere length (TL) and pulmonary fibrosis. To the best of our knowledge, no other families or individuals have been reported to have pathogenic variants in ZCCHC8 and TBD . However, in this abstract, we present data from a second family discovered to harbor a pathogenic variant in ZCCHC8 and to have symptoms of TBD. Methods Family members provided informed consent for genetic testing and underwent trio-based whole-genome sequencing (WGS). DNA isolated from fkin-derived fibroblasts was analyzed in the proband, while DNA from whole blood was used for the parents. To measure TL, we employed Computel (Nersisyan L. et al., 2015) and compared the mean TL to a cohort of patients who also underwent WGS to estimate a relative mean TL. Results: The proband was a 14-year-old male who had pancytopenia and elevated ALAT levels at presentation. A bone marrow biopsy showed a hypocellular bone marrow. A liver biopsy revealed mild centrilobular, pericellular, and portal fibrosis, along with mild inflammation in the portal space, these findings were interpreted as liver regeneration following acute hepatitis. Despite thorough investigations, no explanation for the findings was found. The proband had a history of psychogenic non-epileptic seizures. When the patient was around 20 years of age his hair started to gray. At present, the proband is 23 years old and has not experienced any progression of symptoms. Family history revealed that the proband's father and two second-degree relatives on the paternal side of the family had developed pulmonary fibrosis in the fifth and sixth decade of life as well as early grey hair. Thus, the inheritance pattern of disease related to TBD was autosomal dominant. WGS revealed a heterozygous pathogenic variant in ZCCHC8 (NM_017612.5c.557C>T (p.P186L)) present in the proband and the father which was absent in the mother. The variant was the same as reported by Gable et al. (2019). The variant is not present in gnomAD or COSMIC and it is the only reported pathogenic or likely pathogenic ZCCHC8 missense variant in ClinVar to date. Both the proband and the father exhibited short relative mean TL by Computel estimation. Subsequently, Flow-FISH analysis confirmed that the proband's telomere length was below the 1st percentile. Conclusion Here we present a family with a heterozygous germline variant in ZCCHC8 and TBD including pulmonary fibrosis, pancytopenia, early graying of the hair, and liver disease. Thus, we provide strong evidence of an association between TBD and ZCCHC8.

РОЛЬ КУРЕНИЯ В РАЗВИТИИ АРТЕРИАЛЬНОЙ ГИПЕРТОНИИ У БЕРЕМЕННЫХ

Introduction. It is well known about the risk factors (RF) for arterial hypertension in the general population, however, their significance in hypertension is well known, however, their significance in pregnant women has been little studied. The purpose of the study was to evaluate the effect of the most common risk factors on the development of hypertension in pregnant women. Materials and methods. The study group consisted of 312 pregnant women suffering from hypertension, the control group - 358 pregnant women with normal blood pressure. The relative odds (OR) were calculated using the logistic regression method for the following risk factors: age, smoking, family history, and overweight. Results. With overweight (25≤ BMI ≥29.9 kg/m2), the OR for the development of hypertension was 3.1 (1.7-5.8), while with obesity (compared with normal and overweight) it increased to 12 ( 7.6-19.1). With aggravated heredity, the OR was 6.9 (4.7-10.3). OR in pregnant women with aggravated heredity on the paternal side was 5.2 (2.7-10.2), on the maternal side - 7.4 (4.6-11.8), on both parents - 9.3 (3.6 -24.9). In our study, 20% of women in the group with hypertension smoked, which is significantly more than in the group without hypertension - 13%, p=0.01. At the same time, IPI in the group of pregnant women with AH was 7.5 (2.5-15), which was significantly higher than in the control group 1.9 (1-7.5), p<0.001. It was found that smoking increased the OR of developing hypertension in pregnant women by 4.6 times (2.43-9.4). At the same time, with a pack/year index (PLI) of more than 10 (compared with non-smokers), the OR was 13.1 (5.5–29.9), which was statistically significantly higher than with smoking with a PLI ≤10 (compared with non-smokers) OR was only 2.6 (1.6-3.9), p=0.006. When comparing two groups by age, it was found that pregnant women with hypertension were older than those with normal blood pressure (32 (28-36) and 28 (24-32) years, respectively, p=0.002). ROC analysis with a probability of more than 80% determined that age over 33 years is a risk factor for the presence of hypertension in pregnant women. Thus, the risk of developing hypertension in the group of pregnant women over the age of 33 is 1.8 times higher than in the younger age group. When analyzing combinations of several FGs for the development of AH, a multiple increase in the risk in pregnant women was found. Thus, in the group of smoking women under 33 years of age, the OR for the development of AH was 2.2 (1.3-3.8), and in smoking pregnant women over 33 years of age it was 14.1 (5.9-33.5). With a combination of smoking and heredity, the OR increased to 27 (11.5-56), and with a combination of smoking and obesity - 33 (7.3-62). It is noteworthy that with a combination of obesity and hereditary burden, the risk of developing hypertension during pregnancy increased by 54 (6.2-429) times. Conclusion. Smoking ranks third among other risk factors for arterial hypertension in pregnant women, increasing the OR of developing hypertension by 13 times compared to non-smokers. The combination of smoking with other risk factors significantly increased the chance of developing hypertension in pregnant women.

#3639 WHEN WHOLE EXOME SEQUENCING IS NOT GOOD ENOUGH: BACK TO THE ROOTS OR FORWARD TO THE FUTURE

Abstract Background and Aims Over the last few years, massively parallel sequencing (MPS) has been established in genetic diagnostics, where large virtual panels of candidate genes can be screened on a whole exome basis. This has enabled large analyses for most medical indications, including renal genetic diseases. The 25 year old, index female patient was referred for disease clarification. Both non-related parents suffered from end-stage renal disease, with kidney failure in mid adulthood and familiar cystic disease in both the maternal and paternal lines. An external genetic analysis applying MPS on a restricted panel of genes retrieved no conclusive result, apart from two variants in the UMOD gene, classified as class 3 and 4 following ACMG criteria. Method Whole exome sequencing (WES), linkage analysis, haplotype reconstruction, whole genome sequencing (WGS), long-range PCR (LR-PCR). Results The detailed pedigree of the family displayed an autosomal dominant disease with several family members reaching end-stage kidney disease on both the maternal and paternal sides. The maternal family is characterized by polycystic disease of the kidney and most profoundly the liver, with two female members already liver transplanted and one on the waiting list. The paternal family shows more unspecific chronic kidney disease (CKD) with multiple cysts in the kidney, but not in the liver. Two male members reported gout attacks, before the knowledge of CKD. We consented 12 family members for research studies and collected blood for DNA. Contemporary MPS of a virtual panel for cystic diseases (> 60 genes, i.e. PKD1 and PKD2, all known genes for cystic liver disease) in the index patient did not yield a conclusive result, apart from the previously reported UMOD variants [c.464G>A, p.(Cys155Tyr) and c.907G>C, p.(Asp303His)]. These variants both segregated in the paternal family, defining them as lying in cis on one allele. WES was performed on a trio of three affected family members of the maternal family, yielding no further result. Linkage analysis showed 9 peaks with a LOD score above 2.0. One peak is situated on chromosome 16, containing the candidate genes PKD1 and IFT140. WGS revealed the heterozygous variant c.2180T>C, p.(Leu727Pro) in exon 11 of PKD1, which has been reported as causative numerous times in the past. Conventional LR-PCR, which is designed to acknowledge the highly homologous regions of the 6 pseudogenes of PKD1, also retrieved the PKD1 variant, which was not called by MPS. Comparing the sequence reads of the WES with the WGS, the PKD1 variant was detected in 12% in the former, whereas complete detection was achieved in the latter. Since the cutoff for calling variants in WES was set to 20%, the PKD1 variant was not visible to the genetic analyst. The index patient indeed inherited both diseases from her parents, giving her the simultaneous diagnoses of ADPKD and ADTKD(-UMOD). Conclusion ADPKD is one of the most frequent genetic diseases of the human, with PKD1 being involved in > 80% of cases. With the apparent ease of modern technology, increasingly ADPKD families are presented for genetic consultation, also to non-specialized centers. It is tempting to use MPS considering the number of candidate genes and the size of PKD1 (46 exons). However, a negative result should be supported either by LR-PCR or WGS, taking the profound difficulties with the 6 pseudogenes of PKD1 into consideration. It is not known whether the predominance of liver disease in this family with the PKD1 c.2180T>C variant implicates a genotype-phenotype correlation, or whether other (genetic) modifiers may press for a liver phenotype. The renal prognosis of the index case is feared to be worse baring both diseases, even with the pathogeneses being different with a ciliopathy (ADPKD) and a toxic proteinopathy (ADTKD-UMOD), respectively. Since both affected genes are situated on the respective chromosomes 16, the patient bares a 100% risk of receiving children with an adult onset kidney disease, where pre-implantation technology will not solve this specific problem.

An Outstanding Rapid Clinical Response to Olaparib in A Patient with gBRCA2m Fungating Breast Cancer: A Case Report

Background: Breast cancer is a heterogeneous, phenotypically complex disease made up of various biologic subgroups with unique behaviors and therapeutic responses. Noted that despite lack of a cure for metastatic breast cancer (MBC), there have been appreciable advancements in survival that have occurred at the same time as newer systemic treatments. BRCA1 or BRCA2 mutations cause homologous recombination deficient (HRD) cells, which are vulnerable to PARPi agent treatment. Case Report: This case report presents a 40 years old single female, known case of multiple co-morbidities who was diagnosed with Bilateral breast cancer in June 2022. She has a Positive family history of malignancy; mother died from endometrial cancer and aunt from paternal side has breast cancer. She underwent needle core biopsy from her Right breast mass, which revealed Invasive high-grade ductal carcinoma with metaplastic features (foci of keratinizing squamous differentiation, and myxoid stromal change). DCIS, of intermediate and high grades and a solid pattern, was noted, focally suspicious for lymphovascular invasion, Triple negative (ER negative (<1%), PR negative (<1%) and her-2 (+2) FISH negative (Her-2 Low), KI 67= 70%. Left breast mass Biopsy done on 12/9/2022 showed Invasive Lobular carcinoma, grade 3, ER negative, PR negative, Her-2 +1, KI 67=70%, BRCA2 POSITIVE & PDL1 CPS score 10%. Staging positron emission tomography scan done on 10 October 2022. She had a Large hypermetabolic fungating right breast mass infiltrating the chest wall, consistent with biopsy-proven malignancy. Additional smaller FDG-avid lesions noted in the right breast. Moreover, she had FDG-avid right axillary and right internal mammary nodal metastases. Mildly FDG-avid left breast mass, consistent with biopsy-proven malignancy. FDG-avid liver and pleural metastases. She was started on PARP inhibitor (Olaparib) on 20/9/2022 after which she had amazing fast clinical response leading to falling off the large fungating mass. Conclusion: The chance of developing breast and ovarian cancer is extremely elevated if one possesses BRAC 1 or BRCA 2 mutation. In this situation, PARP inhibitors, mutation-targeted therapy, has better outcomes in reducing the morbidity and mortality associated with metastatic breast cancer (Olaparib).

Homotypical and Heterotypical Intergenerational Continuity of Child Maltreatment: Evidence from a Cohort of Families Involved with Child Protection Services.

Child maltreatment (CM) in one generation can predict CM in the next generation, a concept known as intergenerational continuity. Yet, the form taken by the intergenerational continuity of CM remains unclear and fathers are mostly absent from this literature. This longitudinal study aimed to document patterns of intergenerational continuity of substantiated CM, on the maternal and paternal sides, by examining the presence of: homotypical CM, which is the same type of CM in both generations; and heterotypical CM, which is different CM types in both generations. The study included all children substantiated for CM with the Centre Jeunesse de Montréal between 1 January 2003, and 31 December 2020, with at least one parent who was also reported to that agency during their childhood (n = 5861 children). The cohort was extracted using clinical administrative data, and logistic regression models were tested with the children's CM types as the dependent variables. Homotypical continuity was found for: (1) physical abuse on the paternal side; (2) sexual abuse on the maternal side; and (3) exposure to domestic violence on the maternal side. Heterotypical continuity was also prevalent, but to a lesser extent. Interventions helping maltreated parents overcome their traumatic past are essential to foster intergenerational resilience.