The study aims to report a rare case of a novel homozygous variant in the LRBA gene, originating from uniparental disomy of paternal origin. This case contributes new clinical data to the LRBA gene variant database.
The study details the case of a 2-year-old child diagnosed in May 2023 at our center with a homozygous LRBA gene variant. Detailed clinical data of the patient were collected, including whole-exome sequencing of peripheral blood mononuclear cells, with parental genetic verification.
The child presented with recurrent respiratory infections and chronic neutropenia, progressing to pancytopenia. Imaging showed splenomegaly and enlarged lymph nodes in the axillary and abdominal regions. Peripheral blood lymphocyte count revealed reduced B cells and NK cells. Elevated cytokine levels of IFN-α and IFN-r were observed. Whole-exome sequencing revealed a nonsense homozygous variant in the LRBA gene, specifically c.2584C>T (p.Gln862Ter). The father exhibited a heterozygous variant at this locus, while no variant was found in the mother. Sample analysis indicated characteristics of uniparental disomy. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant is preliminarily classified as \"Likely pathogenic\". Currently, there are no reports in academic literature regarding this specific variant site.
LRBA gene variants can lead to a rare inborn error of immunity disease. The c.2584C>T (p.Gln862Ter) variant in exon 22 of the LRBA gene is a newly identified pathogenic variant, and the homozygous variant caused by uniparental disomy is exceedingly rare. This case represents the second global report of an LRBA gene function loss due to uniparental disomy abnormalities.

BACKGROUND: Analyses of miscarriage products indicate that the majority of aneuploidies in early developing embryos derive from errors occurring during maternal meiosis and the paternal contribution is less than 10%. Our aim was to assess the aneuploidy (mainly monosmies) frequencies at the earliest stages of embryo development, 3 days following fertilization during In vitro fertilization (IVF) treatments and to elucidate their parental origin. Later, we compared monosomies rates of day 3 to those of day 5 as demonstrated from Preimplantation Genetic Testing for Structural chromosomal Rearrangement (PGT-SR) results.
METHODS: For a retrospective study, we collected data of 210 Preimplantation Genetic Testing for Monogenic Disorder (PGT-M) cycles performed between years 2008 and 2019.This study includes 2083 embryos, of 113 couples. It also included 432 embryos from 90 PGT-SR cycles of other 45 patients, carriers of balanced translocations. Defining the parental origin of aneuploidy in cleavage stage embryos was based on haplotypes analysis of at least six informative markers flanking the analyzed gene. For comprehensive chromosomal screening (CCS), chromosomal microarray (CMA) and next generation sequencing (NGS) was used.
RESULTS: We inspected haplotype data of 40 genomic regions, flanking analyzed genes located on 9 different chromosomes.151 (7.2%) embryos presented numerical alterations in the tested chromosomes. We found similar paternal and maternal contribution to monosomy at cleavage stage. We demonstrated paternal origin in 51.5% of the monosomy, and maternal origin in 48.5% of the monosomies cases.
CONCLUSIONS: In our study, we found equal parental contribution to monosomies in cleavage-stage embryos. Comparison to CCS analyses of PGT-SR patients revealed a lower rate of monosomy per chromosome in embryos at day 5 of development. This is in contrast to the maternal dominancy described in studies of early miscarriage. Mitotic errors and paternal involvement in chemical pregnancies and IVF failure should be re-evaluated. Our results show monosomies are relatively common and may play a role in early development of ART embryos.

OBJECTIVE: the aim of our study was to assess the contribution of quantitative fluorescent polymerase chain reaction (QF-PCR) and pathology studies in the diagnosis of diandric triploidies/partial hydatidiform moles.
METHODS: this study included all fet al triploidies diagnosed by QF-PCR in chorionic villi or amniotic fluid in the 2 centers of BCNatal in which a maternal saliva sample was used to establish its parental origin. Pathology studies were performed in products of conception and concordance between a partial hydatidiform mole diagnosis and the finding of a diandric triploidy was assessed.
RESULTS: among 46 fetal triploidies, found in 13 ongoing pregnancies and in 33 miscarriages, there were 26 (56%) diandric triploidies. Concordant molecular (diandric triploidy) and pathology results (partial mole) were achieved in 14 cases (54%), while in 6 cases (23%) pathology studies were normal, and in the remaining 6 cases (23%) pathology studies could not be performed because miscarriage was managed medically.
CONCLUSIONS: diandric triploidy is associated with partial hydatidiform mole and its diagnosis is crucial to prevent the development of persistent trophoblastic disease. QF-PCR analysis in chorionic villi or amniotic fluid provides a more accurate diagnosis of the parental origin of triploidy than the classical pathology studies.

OBJECTIVE: We present molecular cytogenetic characterization of a de novo chromosome 1q41-q42.11 microdeletion of paternal origin in a mentally retarded child of a family requesting for genetic counseling of the future pregnancy.
METHODS: A 43-year-old, gravida 1, para 1, woman, who had a 15-year-old son with mental retardation, planned to have another normal child and requested for genetic counseling of the future pregnancy. Her husband was 48 years old. The 15-year-old boy had a body height of 148 cm (<3rd centile) and a body weight of 40 Kg (<35th centile). He had facial dysmorphism, mental retardation, scoliosis, abnormal gaits, tetralogy of Fallot, pulmonary stenosis and autism but did not have any history of epilepsy. Cytogenetic analysis of the boy and the parents revealed normal karyotypes. Array comparative genomic hybridization (aCGH) analysis of the family revealed a de novo 2.028-Mb 1q41-q42.11 microdeletion, or arr 1q41q42.11 (222,571,596-224,599,234) × 1.0 [GRCh37 (hg19)], encompassing 13 Online Mendelian Inheritance in Man (OMIM) genes including DISP1, SUSD4, FBXO28, TP53BP2 and WDR26 in the child. Quantitative fluorescent polymerase chain reaction analysis confirmed a paternal origin of the deletion. Fluorescence in situ hybridization analysis confirmed a 1q41 deletion.
CONCLUSIONS: Genetic counseling of the parents who have a previous child with mental retardation and who wish to have another normal child in the future pregnancy should include genetic studies, and aCGH is useful under such a circumstance.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a de novo 3.19-Mb chromosome 14q32.13-q32.2 deletion of paternal origin.
METHODS: A 36-year-old woman underwent amniocentesis at 20 weeks of gestation because of an advanced maternal age. Her husband was 36 years old. Amniocentesis revealed a karyotype of 46,XY,del(14)(q32.1q32.2). Simultaneous array comparative genomic hybridization (aCGH) analysis showed the result of a 14q32.13-q32.2 deletion. Prenatal ultrasound was unremarkable. The parental karyotypes were normal and did not have such a deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. aCGH was applied on the DNA extracted from cord blood. Polymorphic DNA marker analysis was applied on the DNAs extracted from placenta and parental bloods. aCGH confirmed a 3.19-Mb 14q32.13-q32.2 deletion or arr 14q32.13q32.2 (96,151,751-99,341,476) × 1.0 [GRCh37 (hg19)] encompassing 10 Online Mendelian Inheritance in Man (OMIM) genes of TCL1B, TCL1A, TUNAR, BDKRB2, BDKRB1, ATG2B, GSKIP, AK7, PAPOLA and VRK1. Polymorphic DNA marker analysis confirmed a paternal origin of a de novo interstitial distal 14q deletion.
CONCLUSIONS: Determination of the paternal origin of a prenatally detected de novo interstitial distal 14q deletion by polymorphic DNA marker analysis in this case is significant, and the information acquired is useful for genetic counseling, especially when amniocentesis is performed because of an advanced maternal age.

OBJECTIVE: We present detection of paternal origin of fetal trisomy 21 in a pregnancy with isolated ventriculomegaly but without advanced parental age.
METHODS: A 29-year-old pregnant woman was admitted to the hospital at 18 weeks of gestation for tocolytic treatment because of irregular uterine contractions. Her husband was 30 years old. The couple had a healthy daughter. Prenatal ultrasound incidentally found isolated ventriculomegaly, and subsequent amniocentesis revealed a karyotype of 47,XX,+21 in 20/20 colonies of cultured amniocytes. The pregnancy was terminated, and the fetus manifested characteristic craniofacial appearance of Down syndrome and hyposplastic middle phalanx of the fifth finger. Postnatal polymorphic DNA marker analysis on the DNAs extracted from the cord blood and parental bloods using quantitative fluorescent polymerase chain reaction (QF-PCR) showed a paternal origin of fetal trisomy 21. The father had a karyotype of 46, XY in 40/40 blood lymphocytes.
CONCLUSIONS: QF-PCR is useful for rapid confirmation of prenatally detected fetal trisomy 21 and determination of paternal origin of fetal trisomy 21 especially in pregnancies with fetal structural abnormalities but without advanced parental age.

OBJECTIVE: We present detection of paternal origin of fetal trisomy 18 in a pregnancy conceived by assisted reproductive technology (ART) and in vitro fertilization (IVF).
METHODS: A 39-year-old woman underwent ART and IVF because of primary infertility. The woman was infertile because of myoma and endometriosis. Her husband was 39 years old, and the sperm analysis was normal. The couple was phenotypically normal. This pregnancy was conceived successfully by IVF. She received non-invasive prenatal testing at 11 weeks of gestation, the result showed a high risk for trisomy 18. She underwent chorionic villus sampling at 12 weeks of gestation, and the result was 47,XY,+18 in 24/24 cultured chorionic villi cells. Prenatal ultrasound findings were unremarkable. She underwent amniocentesis at 17 weeks of gestation, and the result was 47,XY,+18 in 20/20 colonies of cultured amniocytes. The pregnancy was subsequently terminated. Postnatal cytogeneic analysis confirmed the prenatal diagnosis. Polymorphic DNA marker analysis on the DNAs extracted from the umbilical cord and parental bloods showed a paternal origin of the extra chromosome 18, indicating a paternal origin of fetal trisomy 18. Cytogenetic analysis of paternal blood revealed a karyotype of 46,XY.
CONCLUSIONS: Fetal trisomy 18 in pregnancies conceived by ART may be of paternal origin, and determination of paternal origin by polymorphic DNA marker analysis is useful for genetic counseling under such a circumstance.

BACKGROUND: Migrant women\'s overall increased risk of adverse pregnancy outcomes is well known. The aim of this study was to investigate possible associations between stillbirth and maternal country of birth and other migration related factors (paternal origin, reason for immigration, length of residence and birthplace of firstborn child) in migrant women in Norway.
METHODS: Nationwide population-based study including births to primiparous and multiparous migrant women (n = 198,520) and non-migrant women (n = 1,156,444) in Norway between 1990 and 2013. Data from the Medical Birth Registry of Norway and Statistics Norway. Associations were investigated by multiple logistic regression and reported as odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: Primiparous women from Sri-Lanka and Pakistan, and multiparous women from Pakistan, Somalia, the Philippines and Former Yugoslavia had higher odds of stillbirth when compared to non-migrant women (adjusted OR ranged from 1.58 to 1.79 in primiparous and 1.50 to 1.71 in multiparous women). Primiparous migrant women whose babies were registered with Norwegian-born fathers had decreased odds of stillbirth compared to migrant women whose babies were registered with foreign-born fathers (aOR = 0.73; CI 0.58-0.93). Primiparous women migrating for work or education had decreased odds of stillbirth compared to Nordic migrants (aOR = 0.58; CI 0.39-0.88). Multiparous migrant women who had given birth to their first child before arriving in Norway had higher odds of stillbirth in later births in Norway compared with multiparous migrant women who had their first child after arrival (aOR = 1.28; CI 1.06-1.55). Stillbirth was not associated with length of residence in Norway.
CONCLUSIONS: This study identifies sub-groups of migrant women who are at an increased risk of stillbirth, and highlights the need to improve care for them. More attention should be paid to women from certain countries, multiparous women who had their first baby before arrival and primiparous women whose babies have foreign-born fathers.

With its vast territory and complex natural environment, China boasts rich cattle genetic resources. To gain the further insight into the genetic diversity and paternal origins of Chinese cattle, we analyzed the polymorphism of Y-SNPs (UTY19 and ZFY10) and Y-STRs (INRA189 and BM861) in 34 Chinese cattle breeds/populations, including 606 males representative of 24 cattle breeds/populations collected in this study as well as previously published data for 302 bulls. Combined genotypic data identified 14 Y-chromosome haplotypes that represented three haplogroups. Y2-104-158 and Y2-102-158 were the most common taurine haplotypes detected mainly in northern and central China, whereas the indicine haplotype Y3-88-156 predominates in southern China. Haplotypes Y2-108-158, Y2-110-158, Y2-112-158 and Y3-92-156 were private to Chinese cattle. The population structure revealed by multidimensional scaling analysis differentiated Tibetan cattle from the other three groups of cattle. Analysis of molecular variance showed that the majority of the genetic variation was explained by the genetic differences among groups. Overall, our study indicates that Chinese cattle retain high paternal diversity (H = 0.607 ± 0.016) and probably much of the original lineages that derived from the domestication center in the Near East without strong admixture from commercial cattle carrying Y1 haplotypes.

To further probe into the paternal origins and domestication area of swamp buffaloes, we examined Y-chromosome diversity of 482 bulls representing 22 populations from China and Southeast Asia. A total of 40 bovine Y-chromosome-specific microsatellite (Y-STR) markers were screened in this study. The results showed that seven Y-STR markers (UMN2405, UMN0504, UMN0103, UMN1307, BC1.2, UMN0304 and INRA008) were specific and polymorphic in male swamp buffaloes, which can define 9 Y-haplotypes corresponding to four Y-haplogroups (Y1, Y2, Y3 and Y4). Haplogroup Y1 was predominant (83.4%) in all swamp buffalo populations, indicating haplogroup Y1 was the major domestication event of swamp buffalo. In addition, the abundant genetic background and backbone of haplogroup Y1 suggested Yangtze Valley as the major domestication area of swamp buffalo. Interestingly, haplogroup Y4 was only confined in Hainan Island which was more ancient than other haplogroups. We hypothesized that haplogroup Y4 was the descendants of the wild Asian buffalo trapped on Hainan Island in prehistoric glacier period and preserved by later introgression into domesticated cows after the domestication. In conclusion, our findings revealed four divergent paternal origins in swamp buffaloes based on Y-STR markers.