Aleksandar Rajkovic's research while affiliated with University of California, San Francisco and other places

Publications (236)

Article
Reproductive longevity is associated with health outcomes. Early menopause, loss of ovarian function, and male infertility are linked to shorter lifespan and increased adverse health outcomes. Here we examined the extragonadal effects of whole animal loss of Sohlh1 gene in mice, a well-described mouse model of female and male infertility. Sohlh1 en...
Chapter
A basic understanding of human genetics is vital for all those working in the field of assisted human reproduction. Genetic makeup can hamper reproduction and insight into this is making genetic diagnosis and counselling increasingly important. This fully updated textbook continues the clear structure of the original edition, beginning with a chapt...
Chapter
A basic understanding of human genetics is vital for all those working in the field of assisted human reproduction. Genetic makeup can hamper reproduction and insight into this is making genetic diagnosis and counselling increasingly important. This fully updated textbook continues the clear structure of the original edition, beginning with a chapt...
Article
Full-text available
STUDY QUESTION What are the cellular composition and single-cell transcriptomic differences between myometrium and leiomyomas as defined by single-cell RNA sequencing? SUMMARY ANSWER We discovered cellular heterogeneity in smooth muscle cells (SMCs), fibroblast and endothelial cell populations in both myometrium and leiomyoma tissues. WHAT IS KNO...
Article
Plasma cell neoplasms (PCN) are associated with characteristic chromosomal aberrations of diagnostic and prognostic significance. The presence of a small proportion of neoplastic cells is a drawback in application of karyotyping and fluorescence in situ hybridization (FISH) for evaluation of bone marrow aspirates. Analysis of samples enriched for C...
Article
An equitable approach by the American College of Medical Genetics and Genomics (ACMG) has recently recommended carrier screening for genes associated with moderate to severe autosomal recessive conditions with a carrier frequency of ≥1/200 in the Genome Aggregation Database exomes (gnomADv2.0.2). We analyzed carrier frequencies in gnomADv3.1.1 geno...
Article
(Abstracted from Genet Med 2021;23:1793–1806) Carrier screening can be used to determine if an individual or couple is at risk to have a child with an autosomal recessive or X-linked genetic disorder. The American College of Medical Genetics and Genomics (ACMG) last published documents specific to carrier screening in 2004 and 2008.
Article
In mice, following the proliferation of primordial germ cells, oogonia enter meiosis circa embryonic day 13 and are then referred to as oocytes in the embryonic mouse ovary. Oocytes in the embryonic ovary exist in clusters, surrounded by epithelial pregranulosa cells [1]. Germ cell cyst breakdown results in the envelopment of individual oocytes by...
Article
Context Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. Objective We sought to identify and characterize patients...
Chapter
Preimplantation genetic testing (PGT) comprises a wide range of molecular techniques that are utilized during assisted reproduction and in vitro fertilization treatment for a range of indications prior to implantation. PGT is used to evaluate embryos at risk for monogenic diseases, chromosome structural rearrangements, and chromosome aneuploidies....
Article
Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which have key functions during embryogenesis and adult phys...
Article
Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscu...
Article
Patients with reciprocal balanced translocations (RBT) have a risk for recurrent pregnancy losses (RPL), affected child, and infertility. Currently, genetic counseling is based on karyotypes found among the products of conception (POC), although factors influencing the success of assisted reproductive technologies (ART) in RBT couples are not estab...
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Full-text available
Background Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early‐onset non‐progressive involuntary movements. Although NKX2‐1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2‐1 gene, indicating that mutations of non‐coding regulatory elements of NKX2‐1 ma...
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Full-text available
The MCM8/9 complex is implicated in aiding fork progression and facilitating homologous recombination (HR) in response to several DNA damage agents. MCM9 itself is an outlier within the MCM family containing a long C-terminal extension (CTE) comprising 42% of the total length, but with no known functional components and high predicted disorder. In...
Preprint
Full-text available
Uterine leiomyomas are the most common tumors of the female reproductive tract with significant morbidity that includes excessive bleeding, infertility and pregnancy complications. The origin and cellular composition of leiomyomas is controversial, yet very important in better understanding the pathogenesis of these tumors. We applied single-cell R...
Article
Full-text available
There has been significant concern regarding fertility and reproductive outcomes during the SARS-CoV2 pandemic. Recent data suggests a high concentration of SARS-Cov2 receptors, ACE2 or TMPRSS2 , in nasal epithelium and cornea, which explains person-to-person transmission. We investigated the prevalence of SARS-CoV2 receptors among reproductive tis...
Article
Objectives: To investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL) and to determine biological mechanisms contributing to RPL. Methods: During a 20-year period, 12 096 POC samples underwent classical chromosome analysis...
Preprint
Members of the differential screening-selected gene aberrative in neuroblastoma (DAN) protein family are developmentally conserved extracellular binding proteins that antagonize bone morphogenetic protein (BMP) signaling. This protein family includes the Gremlin proteins, GREM1 and GREM2, which are known to have key functions during embryogenesis a...
Article
In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single‐nucleotide variants (SNVs) are observed in one of 59 genes associated with a life‐threatening, medically actionable condition. Little is known about th...
Preprint
The MCM8/9 complex is implicated in aiding fork progression and facilitating homologous recombination (HR) in response to several DNA damage agents. MCM9 itself is an outlier within the MCM family containing a long C-terminal extension (CTE) comprising 42% of the total length, but with no known functional components and high predicted disorder. In...
Preprint
Objectives: To investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL), and to determine biological mechanisms contributing to RPL. Design: Retrospective cohort study. Setting: University-affiliated medical center. Patients: D...
Preprint
There has been significant concern regarding fertility and reproductive outcomes during the SARS-CoV2 pandemic. Recent data suggests a high concentration of SARS-Cov2 receptors, ACE2 or TMPRSS2, in nasal epithelium and cornea, which explains person-to-person transmission. We investigated the prevalence of SARS-CoV2 receptors among reproductive tiss...
Article
Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is...
Article
Full-text available
Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is...
Article
Full-text available
Male factor infertility is a problem in today’s society but many underlying causes are still unknown. The generation of a conditional Sertoli cell (SC)-specific connexin 43 (Cx43) knockout mouse line (SCCx43KO) has provided a translational model. Expression of the gap junction protein Cx43 between adjacent SCs as well as between SCs and germ cells...
Article
About 10% of women of reproductive age are unable to conceive or carry a pregnancy to term. Female factors alone account for at least 35% of all infertility cases and comprise a wide range of causes affecting ovarian development, maturation of oocytes, and fertilization competence, as well as the potential of a fertilized egg for preimplantation de...
Article
Purpose: Sex-biased expression of genes on the X chromosome is accomplished by a complex mechanism of dosage regulation that leads to anatomical and physiological differences between males and females. Copy-number variations (CNVs) may impact the human genome by either affecting gene dosage or disturbing a chromosome structural and/or functional i...
Article
To the Editor In the JAMA Insights Clinical Update on noninvasive prenatal screening using cfDNA,¹ the authors discussed test failures that occur when the fraction of fetal DNA is too low, leading to a diagnostic test.² The cited fetal fraction threshold of 4% is historical and modeled and follows empirical reasoning. However, a standard method for...
Chapter
Assisted reproductive technologies presently incorporate a number of cutting edge molecular techniques. Preimplantation genetic testing is used to screen for aneuploidies, diagnose monogenic diseases, and analyze chromosome structural rearrangements. In this chapter, we overview existing approaches to the genetic testing of embryos, as well as bene...
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Full-text available
Purpose To investigate the potential genetic etiology of premature ovarian insufficiency (POI). Methods Whole-exome sequencing (WES) was done on DNA samples from women diagnosed with POI. Mutations identified were analyzed by in silico tools and were annotated according to the guidelines of the American College of Medical Genetics and Genomics. Pl...
Article
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We performed whole exome sequencing to identify an unknown genetic cause of azoospermia and male infertility in a large Pakistani family. Three infertile males were subjected to semen analysis, hormone testing, testicular histology, ultrasonography, karyotyping, Y-chromosome microdeletion and CFTR testing. The clinical testing suggested a diagnosis...
Article
Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelo...
Data
SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex determination. We identified two...
Article
Study question: What is the prevalence of somatic chromosomal instability among women with idiopathic primary ovarian insufficiency (POI)? Summary answer: A subset of women with idiopathic POI may have functional impairment in DNA repair leading to chromosomal instability in their soma. What is known already: The formation and repair of DNA do...
Article
Full-text available
Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a referenc...
Article
SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two...
Article
Full-text available
Background: Hypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progressi...
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Full-text available
The transcriptional factor MED12 is part of the essential mediator transcriptional complex that acts as a transcriptional coactivator in all eukaryotes. Missense gain of function mutations in human MED12 are associated with uterine leiomyomas, yet the role of MED12 deficiency in tumorigenesis and reproductive biology has not been fully explored. We...
Article
Inverted isodicentric chromosome 21 is a rare form of chromosomal rearrangement that may result in trisomy 21; sometimes this rearrangement may also lead to segmental monosomy of the terminal long arm of chromosome 21. In this report, we describe the prenatal diagnosis and neonatal follow-up of a child with a paternally derived, de novo isodicentri...
Article
The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF) in women. Specifically, we...
Article
Following migration of primordial germ cells to the genital ridge, oogonia undergo several rounds of mitotic division and enter meiosis at approximately E13.5. Most oocytes arrest in the dictyate (diplotene) stage of meiosis circa E18.5. The genes necessary to drive oocyte differentiation in parallel with meiosis are unknown. Here, we have investig...
Article
Background: The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at le...
Article
Reproductive fitness and its influence on overall health has been a topic of significant study and interest. Multiple studies have found that age at last reproduction associates with overall health. Women who conceive later in life are significantly more likely to outlive their peers who are unable to conceive. The mechanisms behind these observati...
Article
We report the first case of distinct, synchronous serous carcinomas of the adnexa arising in a patient with a family history of breast and ovarian cancer and a germline loss of function mutation in BRCA1. Illustrating an exceedingly rare phenomenon of synchronous high-grade carcinomas with distinct histomorphologic, immunohistochemical and cytogene...
Article
Reproduction is essential for the survival of the species and is influenced by external factors such as smoking and exposure to chemotherapy as well as chronic disorders such as obesity and autoimmunity. Reproductive senescence, such as menopause, is also dependent on multiple intrinsic genetic factors. Reproductive aging is not isolated from an ov...
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Full-text available
Purpose of Review Uterine Leiomyomas are one of the most common clinically relevant solid tumors occurring in women of reproductive age. Until recently not much was known about the genetic etiology of these tumors. This review focusses on some of the past and present findings which have greatly contributed to a better understanding of the genetics...
Article
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Most clinicians are not prepared to provide integrated personal care to address all the clinical needs of women with primary ovarian insufficiency. Design thinking is an engineering methodology used to develop and evaluate novel concepts for systems operation. Here we articulate the need for a seamlessly integrated mobile health system to support g...
Article
Objective: To determine the genomic signatures of human uterine leiomyomas and prevalence of MED12 mutations in human uterine leiomyosarcomas. Design: Retrospective cohort study. Setting: Not applicable. Patient(s): This study included a set of 16 fresh frozen leiomyoma and corresponding unaffected myometrium specimens as well as 153 leiomyo...
Article
Full-text available
Objective: To assess the frequency of variants, including biallelic pathogenic variants, in MCM8 and MCM9, other genes related to MCM8/9 and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design: MCM8, MCM9 and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced am...
Article
Hand?Foot?Genital syndrome is a rare autosomal dominant condition characterized by distal limb anomalies and urogenital malformations. This disorder is associated with loss-of-function mutations in the HOXA13 gene. HOXA13 plays an important role in the development of distal limbs and lower genitourinary tract of the fetus. We report a novel familia...
Data
Chromatin immunoprecipitation primers. Primers used for amplification of chromatin immunoprecipitated from E18.5 fetal mouse ovary are listed here. Primers amplified a 100–200 base pair fragment at the genomic region indicated. (DOCX)
Article
Full-text available
TAF4b is a gonadal-enriched subunit of the general transcription factor TFIID that is implicated in promoting healthy ovarian aging and female fertility in mice and humans. To further explore the potential mechanism of TAF4b in promoting ovarian follicle development, we analyzed global gene expression at multiple time points in the human fetal ovar...
Data
TAF4b targets the promoters of critical meiosis and oogenesis regulators: Wild-type E18.5 ovarian chromatin pulled down by antibodies against TAF4b or IgG and then PCR-amplified using primers against the proximal promoters of Stra8, Dazl, Figlα, Nobox, and a non-genic region upstream of Nobox. “Input” lanes indicate the positive control PCR reactio...
Data
Reduced DAZL protein expression in PND0 Taf4b-deficient ovaries. (A) PND0 wild-type and Taf4b-deficient (B) ovary tissue sections were stained with antibodies against DAZL and TRA98, showing reduced DAZL expression in Taf4b-deficient ovaries. (C) Western blot analysis was used to confirm the immunostaining results, with the blot incubated in primar...
Data
E13.5 wild-type and Taf4b-deficient ovary tissue sections were stained with primary antibody against MVH to visualize germ cells at the start of female meiosis. Both genotypes possess relatively similar numbers of germ cells at this embryonic time. (TIFF)
Data
Synaptonemal Complex Protein 3 configuration during prophase I: Wild-type oocyte meiotic chromosome spreads were prepared and stained with primary antibodies against Synaptonemal Complex Protein 3; configuration of SYCP3 was used to determine prophase I stage, as indicated by the four panels. (TIFF)
Data
Ingenuity pathway analysis of TAF4B-correlated genes. Coordinate gene expression profiles of human fetal ovary over gestational time were analyzed with Pearson Correlations and Ingenuity Pathway Analysis. Human TAF4B was found to be most highly correlated with the expression of a network of meiotic regulators. (XLSX)
Data
Recombinant TAF4b protein purification, polyclonal anti-TAF4b antibody production and antibody purification. (A) Coomassie-stained SDS-PAGE analysis of 6xHis-TAF4bN1 recombinant protein purification. Immunoblot detection of recombinant 6xHis-TAF4bN1 antigen with preimmune and anti-sera from chicken (B) and rabbit (C) (predicted molecular weight of...
Data
Quantitative RT-PCR primers. Primers used for amplification of cDNA from E13.5 fetal mouse ovary are listed here. Primers amplified a 100–200 base pair fragment of the gene indicated. (DOCX)
Article
Over the last decade, several advances in ultrasound techniques, increasing availability of whole genome microarray testing, and overall expansion of our knowledge about the human genome have drastically enhanced our ability to detect chromosomal abnormalities prenatally. Despite that, genotype-phenotype correlation is difficult to establish for ma...
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Full-text available
Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Ho...
Chapter
Clinical Vignette Sarah, a 29-year-old married woman who was given the diagnosis of primary ovarian insuffi ciency two years prior, moved her cursor toward the X in the upper right corner after her exhaustive Google search. She had desperately typed every keyword she could think of in a frustrating attempt to fi nd an experimental therapy capable o...
Chapter
Ovarian folliculogenesis in mammals is a cyclic and dynamic process that involves dramatic change in the size and number of various cell types of the ovary. The oocyte lies at the epicenter of the ovarian follicle, surrounded by the somatic granulosa and thecal cell layers. Oocyte growth and differentiation within the follicles is remarkable and hi...
Article
To evaluate the clinical utility, diagnostic yield and rationale of integrating microarray analysis in the clinical diagnosis of hematological malignancies in comparison with classical chromosome karyotyping/fluorescence in situ hybridization (FISH). G-banded chromosome analysis, FISH and microarray studies using customized CGH and CGH+SNP designs...
Article
Full-text available
Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (MED12) exon 2 variants are associated with uterine leiomyomas; however, the causality of MED12 variants, their genetic mode of action, and their role in genomic instability have not been established. Here, we generated a m...
Article
The human X chromosome contains ~1,600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence hom...
Article
The aim of this study was to survey the opinions of expectant parents regarding prenatal whole-exome sequencing. The study used a questionnaire that focused on acceptability of prenatal whole-exome sequencing to individuals who pursued first-trimester prenatal screening in a tertiary academic medical center. A total of 186 expectant individuals com...
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Full-text available
The early stages of ovarian follicle formation-beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles-are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcripti...
Article
Background: The genetic basis of nonobstructive azoospermia is unknown in the majority of infertile men. Methods: We performed array comparative genomic hybridization testing in blood samples obtained from 15 patients with azoospermia, and we performed mutation screening by means of direct Sanger sequencing of the testis-expressed 11 gene (TEX11...
Article
Deletions spanning the MN1 gene (22q12.1) have recently been proposed as playing a role in craniofacial abnormalities that include cleft palate, as mouse studies have demonstrated that Mn1 haploinsufficiency results in skull abnormalities and secondary cleft palate. We report on four patients (two families) with craniofacial abnormalities and intel...
Article
Background Noninvasive prenatal screening (NIPS) by next-generation sequencing of cell free DNA (cfDNA) in maternal plasma is used to screen for common aneuploidies such as trisomy 21, in high risk pregnancies. NIPS can identify fetal genomic microdeletions, however sensitivity and specificity have not been systematically evaluated. Commercial comp...
Article
Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization...
Article
Full-text available
Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with pr...
Article
Rapid progress in genomic medicine in recent years has made it possible to diagnose subtle genetic abnormalities in a clinical setting on routine basis. This has allowed for detailed genotype-phenotype correlations and the identification of the genetic basis of many congenital anomalies. In addition to the availability of chromosomal microarray ana...
Article
Cryptorchidism is the most common genital problem encountered in males and is associated with many chromosomal disorders; however, the genetic factors are mostly unknown. To delineate critical genes affecting testicular migration, we performed genotype–phenotype correlation in patients with deletions involving the proximal short arm of chromosome 1...