Prader-Willi (PWS) and Angelman (AS) syndromes were the first examples in humans with errors in genomic imprinting, usually from de novo 15q11-q13 deletions of different parent origin (paternal in PWS and maternal in AS). Dozens of genes and transcripts are found in the 15q11-q13 region, and may play a role in PWS, specifically paternally expressed SNURF-SNRPN and MAGEL2 genes, while AS is due to the maternally expressed UBE3A gene. These three causative genes, including their encoding proteins, were targeted. This review article summarizes and illustrates the current understanding and cause of both PWS and AS using strategies to include the literature sources of key words and searchable web-based programs with databases for integrated gene and protein interactions, biological processes, and molecular mechanisms available for the two imprinting disorders. The SNURF-SNRPN gene is key in developing complex spliceosomal snRNP assemblies required for mRNA processing, cellular events, splicing, and binding required for detailed protein production and variation, neurodevelopment, immunodeficiency, and cell migration. The MAGEL2 gene is involved with the regulation of retrograde transport and promotion of endosomal assembly, oxytocin and reproduction, as well as circadian rhythm, transcriptional activity control, and appetite. The UBE3A gene encodes a key enzyme for the ubiquitin protein degradation system, apoptosis, tumor suppression, cell adhesion, and targeting proteins for degradation, autophagy, signaling pathways, and circadian rhythm. PWS is characterized early with infantile hypotonia, a poor suck, and failure to thrive with hypogenitalism/hypogonadism. Later, growth and other hormone deficiencies, developmental delays, and behavioral problems are noted with hyperphagia and morbid obesity, if not externally controlled. AS is characterized by seizures, lack of speech, severe learning disabilities, inappropriate laughter, and ataxia. This review captures the clinical presentation, natural history, causes with genetics, mechanisms, and description of established laboratory testing for genetic confirmation of each disorder. Three separate searchable web-based programs and databases that included information from the updated literature and other sources were used to identify and examine integrated genetic findings with predicted gene and protein interactions, molecular mechanisms and functions, biological processes, pathways, and gene-disease associations for candidate or causative genes per disorder. The natural history, review of pathophysiology, clinical presentation, genetics, and genetic-phenotypic findings were described along with computational biology, molecular mechanisms, genetic testing approaches, and status for each disorder, management and treatment options, clinical trial experiences, and future strategies. Conclusions and limitations were discussed to improve understanding, clinical care, genetics, diagnostic protocols, therapeutic agents, and genetic counseling for those with these genomic imprinting disorders.

Robertsonian translocations (Rob-t) are the most common structural chromosomal abnormalities observed in humans. Cytogenetic analysis remains essential to identify these abnormalities which cannot be identified by currently used DNA-based tests. This study describes the cytogenetic profile and clinical presentations of Rob-t. This was a retrospective observational study of patients with Rob-t who underwent cytogenetic analysis at a tertiary-care center in south India from 2001 to 2019. Rob-t were observed in 88/12,227(0.72%) patients tested including 4/1425 (0.28%) prenatal samples. There were 21 (0.09%) adults and 63 (0.58%) children (M:F = 1.27:1). With 10 types of Rob-t, eight (72.7%) heterologous and two homologous (27.3%). Thirty(34%) were balanced and 58(66%) unbalanced (associated with trisomy). All 21 adults had balanced Rob-t and had recurrent pregnancy loss, infertility/oligospermia, premature ovarian failure or were carrier parents. All unbalanced Rob-t were observed in children with trisomy 21(98.2%) or trisomy 13(1.8%). The der(14;21), der(21;21) and the der(13;14) accounted for 32(36.4%), 22(25%) and 17(19.3%), respectively and the other Rob-t for <6% each; 16(18.2%) der(13;14) were balanced.One child had mosaicism for der(21;21) and a ring chromosome 21. Three more patients had additional abnormalities, namely, t(10;12) (p11.1;q22), 15q microdeletion consistent with Prader-Willi syndrome and mosaic X/XXX. All adults had balanced Rob-t. Unbalanced Rob-t were seen only in children. The unbalanced der(14;21) was our most common Rob-t followed by der(21;21) because the majority were ascertained in children with Down syndrome. The der(13;14) was the most common balanced Rob-t.

Background and Clinical Significance: Prader-Willi syndrome (PWS) is a rare genetic disease caused by imprinted gene dysfunction, typically involving deletion of the chromosome 15q11.2-q13 region, balanced translocation, or related gene mutations in this region. PWS presents with complex and varied clinical manifestations. Abnormalities can be observed from the fetal stage and change with age, resulting in growth, developmental, and metabolic issues throughout different life stages. Case Presentation: We report the prenatal characteristics observed from the second to third trimester of pregnancy in a neonate with PWS. Prenatal ultrasound findings included a single umbilical artery, poor abdominal circumference growth from 26 weeks, normal head circumference and femur length growth, increased amniotic fluid volume after 30 weeks, undescended fetal testicles in the third trimester, small kidneys, and reduced fetal movement. The male infant was born at 38 weeks of gestation with a birth weight of 2580 g. He had a weak cry; severe hypotonia; small eyelid clefts; bilateral cryptorchidism; low responsiveness to medical procedures such as blood drawing; and poor sucking, necessitating tube feeding. Blood methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) showed paternal deletion PWS. Notably, this case revealed two previously unreported prenatal features in PWS: a single umbilical artery and small kidneys. Conclusions: Through literature review and our case presentation, we suggest that a combination of specific sonographic features, including these newly identified markers, may aid clinicians in the early diagnosis of PWS.

Prader-Willi syndrome (PWS) is primarily caused by a paternal microdeletion of the 15q11-q13 region, maternal uniparental disomy (mUPD) or unbalanced translocations. The MKRN3 gene, located within 15q11-q13, is a master regulator of pubertal initiation. We aimed to compare variant pubertal onset and progression with recent normative data and to correlate it with abnormal MKRN3 gene status. Age at pubarche, gonadarche, subsequent pubertal progression and bone age (BA) at gonadarche were investigated in 37 PWS patients (18 females) who already entered pubarche and/or gonadarche with median age 11.1 (95% CI: 6.4 - 18.8) years. All patients were re-tested to confirm genetic subtypes of PWS. The MKRN3 gene was analyzed using single gene sequencing. Out of 37 subjects, 22 had microdeletion and 15 mUPD. Regardless of genetic subtypes and MKRN3 gene status, no correlation between genotypes and the pubertal pattern was found. They initiated pubarche early - girls at 7.4 (95%CI:6.4-8.4), and boys at 9.2 (8.2-10.2) years. The subsequent progression from PH2 to PH4 (pubic hair development) was prolonged to 3.7 years in girls (1.5-5.9;p<0.05), and 2.9 in boys (2.2-3.6;p<0.001). The age at gonadarche was adequate - 10.0 years in girls (8.8-11.2), and 11.0 in boys (9.8-12.1). Progression rate of breast development from B2 to B4 was 3.9 (0.2-7.5) years in girls and of testicular volume from 4 ml to 15ml was 3.8 (0.0-8.1) years in boys. The BA at gonadarche is advanced by 0.6 ± 1.1 years (p<0.001). Children with PWS, regardless of the genetic subtype and/or MKRN3 status, had an early pubarche and normally timed gonadarche. Pubarche progression was slower. Advanced BA was significantly correlated with gonadarche.

Uniparental disomy (UPD) is a genetic condition which both copies of a chromosome are inherited from a single parent, potentially leading to imprinting disorders. This study aimed to assess the integration of Short Tandem Repeat (STR) analysis into Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) to assess UPD risk and its impact on selecting euploid embryos for embryo transfer in couples with chromosomal translocations involving imprinted chromosomes. This study evaluated three couples carrying balanced chromosomal translocations: 45,XX,der(13;14)(q10;q10), 46,XX,t(10;11)(q22;q13), and 45,XY,der(14;15)(q10;q10). STR analysis was performed on trophectoderm (TE) biopsies after Whole Genome Amplification (WGA) after PGT-SR analysis using parental blood samples to assess UPD risk in euploid embryos. Haplotyping was conducted with five to six STR markers specific to each rearranged chromosome to detect UPD in euploid embryos. Of the four embryos analyzed across the three families, two couples had euploid embryos that tested negative for UPD. These embryos were successfully transferred, resulting in the birth of two healthy children. In the third family, the euploid embryo also tested negative for UPD but failed to implant after transfer, resulting in no pregnancy. Despite its rarity, UPD involving imprinted chromosomes poses significant clinical risks, as seen in disorders such as Prader-Willi syndrome and Angelman syndrome. This study highlights the importance of integrating UPD screening into PGT-SR protocols, to detect both heterodisomic and isodisomic UPD events minimizing the risk of severe genetic disorders. Integrating STR-based UPD screening within PGT-SR workflows is a reliable and cost-effective strategy that enhances embryo selection and mitigates the risk of imprinting disorders. This approach improves reproductive outcomes for families with chromosomal rearrangements, offering a practical advancement in assisted reproduction.