Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.

The microbiome is an interactive and fluctuating community of microbes that colonize and develop across surfaces, including those associated with organismal hosts. A growing number of studies exploring how microbiomes vary in ecologically relevant contexts have recognized the importance of microbiomes in affecting organismal evolution. Thus, identifying the source and mechanism for microbial colonization in a host will provide insight into adaptation and other evolutionary processes. Vertical transmission of microbiota is hypothesized to be a source of variation in offspring phenotypes with important ecological and evolutionary implications. However, the life-history traits that govern vertical transmission are largely unexplored in the ecological literature. To increase research attention to this knowledge gap, we conducted a systematic review to address the following questions: (1) How often is vertical transmission assessed as a contributor to offspring microbiome colonization and development? (2) Do studies have the capacity to address how maternal transmission of microbes affects the offspring phenotype? (3) How do studies vary based on taxonomy and life history of the study organism, as well as the experimental, molecular, and statistical methods employed? Extensive literature searches reveal that many studies examining vertical transmission of microbiomes fail to collect whole microbiome samples from both maternal and offspring sources, particularly for oviparous vertebrates. Additionally, studies should sample functional diversity of microbes to provide a better understanding of mechanisms that influence host phenotypes rather than solely taxonomic variation. An ideal microbiome study incorporates host factors, microbe-microbe interactions, and environmental factors. As evolutionary biologists continue to merge microbiome science and ecology, examining vertical transmission of microbes across taxa can provide inferences on causal links between microbiome variation and phenotypic evolution.

BACKGROUND: Miscarriage describes the spontaneous loss of pregnancy before the threshold of viability; the vast majority occur before 12 weeks of gestation. Miscarriage affects one in four couples and is the most common complication of pregnancy. Chromosomal abnormalities of the embryo are identified in ∼50% of first trimester miscarriages; aneuploidy accounts for 86% of these cases. The majority of trisomic miscarriages are of maternal origin with errors occurring during meiotic division of the oocytes. Chromosome segregation errors in oocytes may be sporadic events secondary to advancing maternal age; however, there is increasing evidence to suggest possible maternal germline contributions to this.
UNASSIGNED: The objective of this review was to appraise critically the existing evidence relating to maternal germline factors associated with pregnancy loss secondary to embryo aneuploidy, identify limitations in the current evidence base and establish areas requiring further research.
METHODS: The initial literature search was performed in September 2019 and updated in January 2021 using the electronic databases OVID MEDLINE, EMBASE and the Cochrane Library. No time or language restrictions were applied to the searches and only primary research was included. Participants were women who had suffered pregnancy loss secondary to numerical chromosomal abnormalities of the embryo. Study identification and subsequent data extraction were performed by two authors independently. The Newcastle-Ottawa Scale was used to judge the quality of the included studies. The results were synthesized narratively.
RESULTS: The literature search identified 2198 titles once duplicates were removed, of which 21 were eligible for inclusion in this systematic review. They reported on maternal germline factors having variable degrees of association with pregnancy loss of aneuploid origin. The Online Mendelian Inheritance in Man (OMIM) gene ontology database was used as a reference to establish the functional role currently attributed to the genes reported. The majority of the cases reported and included were secondary to the inheritance of maternal structural factors such as Robertsonian translocations, deletions and insertions. Germline factors with a plausible role in aneuploid pregnancy loss of maternal origin included skewed X-inactivation and CGG repeats in the fragile X mental retardation (FMR1) gene. Studies that reported the association of single gene mutations with aneuploid pregnancy loss were conflicting. Single gene mutations with an uncertain or no role in aneuploid pregnancy loss included mutations in synaptonemal complex protein 3 (SYCP3), mitotic polo-like kinase 4 (PLK4) and meiotic stromal antigen 3 (STAG3) spindle integrity variants and 5,10-methylenetetrahydrofolate reductase (MTHFR).
UNASSIGNED: Identifying maternal genetic factors associated with an increased risk of aneuploidy will expand our understanding of cell division, non-disjunction and miscarriage secondary to embryo aneuploidy. The candidate germline factors identified may be incorporated in a screening panel for women suffering miscarriage of aneuploidy aetiology to facilitate counselling for subsequent pregnancies.

Hb Mizuho is a very rare unstable hemoglobin; here, we describe the clinical history of three Swiss family members with Hb Mizuho together with a systematic review of the previously six published cases. The clinical history of the adult woman we report here is unique since this is the first Hb Mizuho presenting with Moyamoya complications and the first case reported with long-term erythrocyte exchange. The literature review showed that Hb Mizuho was mainly reported as a de novo mutation, with the exception of children descended from known cases. All published patients with this unstable hemoglobin showed severe hemolytic anemia with the exception of one; all were regularly transfused. Patients with higher HbF levels might require fewer transfusions. All patients underwent splenectomy at a median age of 4 years and had variable clinical improvement; some achieved complete resolution of transfusion dependency after splenectomy. Iron overload in Hb Mizuho patients seems to be mainly attributed to transfusions and has less to do with ineffective erythropoiesis. Diagnosis might be challenging; a normal hemoglobin electrophoresis should not rule out the diagnosis of unstable hemoglobin in patients with otherwise unexplained hemolytic anemia. This series shows the enormous utility of using molecular techniques for diagnosis.

OBJECTIVE: The aim of this study is to evaluate the prevalence of maternal complications derived from digoxin treatment and its relationship with digoxinemia, as well as its occurrence in relation to the different treatment doses and therapeutic schemes used.
METHODS: This is a retrospective observational study of women who received digoxin for the treatment of fetal tachyarrhythmia over a 10-year period at the University Hospital Virgen del Rocío (Seville). Data corresponding to the digoxin dose, its duration, serum digoxin levels and electrocardiographic parameters during follow-up were collected. Maternal side effects were reported, and its relationship to the treatment dose as well as digoxinemia. The study is accompanied by a narrative review of related literature.
RESULTS: There were 10 cases eligible. During treatment, as least one symptom or sign was present in 30 % of cases, being in all cases digestive symptoms. In all those cases, the digoxin level was higher than established as therapeutic threshold (2 ng/mL), and all reversed within a maximum of 48 h after the dose decrease. Digoxinemia overdosing (> 2 ng/mL) was observed in 6 women (60 %), one of which reached the toxicity range (> 3 ng/mL). In all cases, normal range was achieved decreasing the dose of digoxin 0.25 mg every 24 h. No patient developed side effects with digoxinemia below 2 ng/mL. No electrocardiographic abnormalities appeared during treatment.
CONCLUSIONS: Digoxin is a safe treatment for management of fetal tachyarrhythmias. Side effects appear frequently when serum digoxin level is over 2 ng/mL, but they are usually mild and self-limited. However, it remains advisable to monitor electrocardiographic changes and digoxinemia through the whole therapy to prevent serious complications related to digoxin toxicity.

OBJECTIVE: We characterized a maternally inherited small supernumerary marker chromosome (sSMC) derived from chromosome 15 according to prenatal detection and made a review on the prenatal sSMC(15) cases with mosaic maternal inheritance.
METHODS: A 29-year-old woman underwent amniocentesis at 19 weeks of gestation due to the high risk of Down syndrome in maternal serum screening. No abnormalities were observed in prenatal ultrasound findings. G-banding analysis revealed a karyotype of 47,XX,+mar. Subsequently, we recalled the couple back for chromosomal analysis. The father\'s karyotype was normal while the mother\'s karyotype was 47,XX,+mar[15]/46,XX[35]. Molecular genetic analysis was utilized to identify the marker chromosome. The chromosomal microarray analysis (CMA) results of the mother showed there existed microduplications in the locus of 14q32.33, 15q21.1, 19p12 and Xq26.2, respectively. Then Fluorescence in situ hybridization (FISH) using specific probes for chromosomes 13/21, 14/22, and 15 was applied on the mother and the fetus. And the marker chromosomes for the mother and the fetus were all finally identified as inv dup(15) (D15Z1++, SNRPN-, PML-), which illustrated that the fetus inherited the sSMC(15) from her mother. Finally, a healthy female infant was delivered with no phenotypic abnormalities at 39 weeks.
CONCLUSIONS: The combined utilization of the molecular genetic technologies, such as FISH and CMA, plays a critical role in the identification of the origins and genetic constitutions of sSMC, which would make a significant contribution to genetic counseling and prenatal diagnosis.

Prader-Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11-q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader-Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15-related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co-occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15-related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.

The influence of maternal body mass index (BMI) on pregnancy and child health outcomes is well characterised, however less is known about paternal BMI. This systematic review investigated the independent effects of increased paternal BMI on conception and pregnancy as well as neonatal and childhood outcomes.
Our systematic search (Sept. 2018) of PubMed, Embase, Cinahl, Web of Science, ProQuest, and OpenThesis resulted in 11,045 hits from which 17 studies met the inclusion criteria (Participants: men Exposure: BMI or waist circumferences Outcomes: associations with time to pregnancy, incidence of infertility, pregnancy loss, pregnancy complications, birthweight and length, childhood weight and height, or incidence of any childhood disease). Studies had to adjust for maternal age and BMI.
Meta-analysis was only possible for infertility which was significantly more prevalent in obese (OR=1.49 95%CI 1.30-1.70) and overweight (OR=1.18 95%CI 1.11-1.26) men. Individual studies showed increased likelihoods of small for gestational age and macrosomia in fathers who had increased BMI - possibly accounting for the general finding of no effect on mean birthweight in other studies. Most studies found increased BMI in fathers correlated with altered growth curves and increased BMI in childhood, while one study found a higher likelihood of autism spectrum disorder.
Our findings support increased paternal BMI negatively affecting pregnancy and child health outcomes. Future studies must include or adjust for paternal contributions, as the longstanding assumption that only maternal factors are relevant is likely to have considerably confounded prior work.

There is evidence showing a positive correlation between prenatal androgens and their effect on the development of central nervous system and the autistic spectrum disorder (ASD) phenotype in offspring of mothers with polycystic ovary syndrome (PCOS). We applied a systematic review to investigate whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease. Major databases from inception until 14th October 2018 were searched. The primary outcome measure was the odds of an ASD diagnosis in children of mothers with diagnosed PCOS, while the secondary outcome was the odds of ASD diagnosis in women with PCOS. Scheduled subgroup analyses were according to the time of birth and maternal age. We assessed the odds ratio (OR), using a random-effects model; heterogeneity was assessed by I2 and τ2 statistics. The quality of the evidence was evaluated using the Newcastle-Ottawa Scale. Ten studies were eligible for inclusion, including a total of 33,887 ASD children and 321,661 non-ASD children. Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring [95% CI: 1.51, 1.83, p = 1.99 × 10-25, 7 studies, I2 = 0%, τ2 = 0]. Women with PCOS were 1.78 times more likely to be diagnosed with ASD (95% CI: 1.10, 2.87, p = 0.0179, 5 studies, I2 = 85.4%, τ2 = 0.2432). Additional analyses did not change the initial result. The overall quality of the evidence was high. The pooled effects size displayed low heterogeneity (I2 = 0%) for the primary outcome. While the heterogeneity in the secondary outcome appears to attenuate when only high quality studies are synthesized, still the result exhibits significant heterogeneity. Τhe available data allowed a subgroup analysis only for classification system for PCOS diagnosis and showed a significant increase of ASD diagnosis in the offspring of women with Read Code and ICD diagnosed PCOS. In conclusion, the available evidence suggests that women with PCOS have increased odds of having a child with ASD, an effect size estimate based on a large number of patients from studies of good quality. Regarding the evidence on the prevalence of ASD in PCOS women, results suggest that women with PCOS are more likely to be diagnosed with ASD.

Complex small marker chromosomes (sSMCs) consist of chromosomal material derived from more than 1 chromosome. Complex sSMCs derived from chromosomes 4 and 21 are rare, with only 7 cases reported. Here, we describe a patient who presented with a complex sSMC derived from a maternal translocation between chromosomes 4 and 21, which was revealed by G-banding, MLPA, and array techniques. The marker chromosome der(21)t(4;21)(q32.1; q21.2)mat is composed of a 25.6-Mb 21pterq21.2 duplication and a 32.1-Mb 4q32.1q35.2 duplication. In comparison to patients with sSMCs derived from chromosomes 4 and 21, our patient showed a similar phenotype with neuropsychomotor developmental delay and facial dysmorphism as the most important finding, being a composition of the findings found in pure 4q and 21q duplications. The wide range of phenotypes associated with sSMCs emphasizes the importance of detailed cytogenomic analyses for an accurate diagnosis, prognosis, and genetic counseling.