Unrelated Infants Research Articles

Novel PLEC variants associated with infantile cholestasis.

Plectin is a cytoskeletal linker of intermediate filaments, encoded by the PLEC gene. Recently, plectin mutations have been identified in a pair of siblings with progressive familial intrahepatic cholestasis. Here, we reported two unrelated infants with plectinopathy causing cholestatic jaundice with novel variants in the PLEC gene. Trio exome sequencing identified compound heterozygous variants in the PLEC gene for each patient: c.71-11768C>T and c.4331G>T (p.Arg1444Leu) in Patient 1, and c.592C>T (p.Arg198Trp) and c.4322G>A (p.Arg1441His) in Patient 2. Immunofluorescence staining of liver samples from both patients revealed scattered signals of plectin in the cytoplasm of hepatocytes and reduced colocalization of plectin and cytokeratin 8. This study not only underscores the involvement of plectin in cholestasis but also highlights the utility of exome sequencing as a powerful diagnostic tool in identifying genetic underpinnings of infantile cholestasis.

Our Journey from Individual Efforts to Nationwide Support: Implementing Newborn Screening for Spinal Muscular Atrophy in Serbia.

Innovative treatments for spinal muscular atrophy (SMA) yield the utmost advantages only within the presymptomatic phase, underlining the significance of newborn screening (NBS). We aimed to establish statewide NBS for SMA in Serbia. Our stepwise implementation process involved technical validation of a screening assay, collaboration with patient organizations and medical professionals, a feasibility study, and negotiation with public health representatives. Over 12,000 newborns were tested during the 17-month feasibility study, revealing two unrelated SMA infants and one older sibling. All three children received therapeutic interventions during the presymptomatic phase and have shown no signs of SMA. No false-negative results were found among the negative test results. As frontrunners in this field in Serbia, we established screening and diagnostic algorithms and follow-up protocols and raised awareness among stakeholders about the importance of early disease detection, leading to the incorporation of NBS for SMA into the national program on 15 September 2023. Since then, 54,393 newborns have been tested, identifying six SMA cases and enabling timely treatment. Our study demonstrates that effective collaborations between academia, non-profit organizations, and industry are crucial in bringing innovative healthcare initiatives to fruition, and highlights the potential of NBS to revolutionize healthcare outcomes for presymptomatic SMA infants and their families.

Effects of acute inhibition of dopamine β-hydroxylase on neural responses to pups in adult virgin male California mice (Peromyscus californicus)

The neural mechanisms underlying paternal care in biparental mammals are not well understood. The California mouse (Peromyscus californicus) is a biparental rodent in which virtually all fathers are attracted to pups, while virgin males vary widely in their behavior toward unrelated infants, ranging from attacking to avoiding to huddling and grooming pups. We previously showed that pharmacologically inhibiting the synthesis of the neurotransmitter norepinephrine (NE) with the dopamine β-hydroxylase inhibitor nepicastat reduced the propensity of virgin male and female California mice to interact with pups. The current study tested the hypothesis that nepicastat would reduce pup-induced c-Fos immunoreactivity, a cellular marker of neural activity, in the medial preoptic area (MPOA), medial amygdala (MeA), basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BNST), brain regions implicated in the control of parental behavior and/or anxiety. Virgin males were injected with nepicastat (75 mg/kg, i.p.) or vehicle 2 hours prior to exposure to either an unrelated pup or novel object for 60 minutes (n = 4–6 mice per group). Immediately following the 60-minute stimulus exposure, mice were euthanized and their brains were collected for c-Fos immunohistochemistry. Nepicastat reduced c-Fos expression in the MeA and MPOA of pup-exposed virgin males compared to vehicle-injected controls. In contrast, nepicastat did not alter c-Fos expression in any of the above brain regions following exposure to a novel object. Overall, these results suggest that the noradrenergic system might influence MeA and MPOA function to promote behavioral interactions with pups in virgin males.

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining Tcells had limited Tcell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype-phenotype correlation assessment.

Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.

Do Wild, Male, Crested Macaques (Macaca nigra) Respond to the Screams of Infants Involved in Agonistic Interactions?

Males may increase their fitness by providing care to offspring or to unrelated infants of female “friends” to maximise future mating. The potential for paternal care depends on paternity certainty, particularly in multi-male, multi-female groups with polygynandrous mating. In crested macaques (Macaca nigra), there seems to be high potential for paternity certainty and need for paternal protection. However, male-mother affiliation (or “friendships”), not paternity, predicts male-infant affiliation, questioning whether males can identify their offspring reliably. Using a Bayesian approach, we investigated male responses to infant screams (N = 2,637) emitted during agonistic interactions with males being the friend of the infant, the friend of the infants’ mother, and/or the father of the infant. Overall, male responses to infant screams were low. Bayesian estimates showed considerable uncertainty; hence, results should be interpreted cautiously. However, males were slightly more likely to react if the infant or its mother was a friend of the male or if the infant was his offspring. Additionally, higher-ranking males were slightly more likely to respond than lower-ranking ones, and screams from infants of lower-ranking females were more likely to be responded to. This might indicate that males assess paternity based on their rank and that they assess the need to intervene. Given the limitations of our study and the uncertainty surrounding our results, future studies are needed before we can draw solid conclusions for crested macaques. Overall, our results are in line with other studies suggesting that male primates provide care to related and unrelated infants.

Early onset critically ill infants with Schaaf-Yang syndrome: a retrospective study from the China neonatal genomes project and literature review.

Schaaf-Yang syndrome (SYS) is a recently identified rare neurodevelopmental disorder characterized by neonatal hypotonia, feeding difficulty, joint contractures, autism spectrum disorder and development delay/intellectual disability. It is mainly caused by truncating variants in maternally imprinted gene MAGEL2 within the Prader-Willi syndrome critical region 15q11-q13. Clinical diagnosis of SYS is difficult for clinicians due to its rarity and highly variable phenotypes, while unique inheritance patterns also complicate genetic diagnosis. To date, no published papers have analyzed the clinical consequences and molecular changes in Chinese patients. In this study, we retrospectively investigated the mutation spectrums and phenotypic features of 12 SYS infants. The data were from a cohort of critically ill infants from the China neonatal genomes project (CNGP), sponsored by Children's Hospital of Fudan University. We also reviewed relevant literature. Six previously reported mutations and six novel pathogenic variations of MAGEL2 were identified in 12 unrelated infants. Neonatal respiratory problems were the major complaint for hospitalization, which occurred in 91.7% (11/12) cases. All babies displayed feeding difficulties and a poor suck postnatally, and neonatal dystonia was present in 11 of the cases; joint contractures and multiple congenital defects were also observed. Interestingly, we found that 42.5% (57/134) of the reported SYS patients, including ours carried variants in the c.1996 site, particularly the c.1996dupC variant. The mortality rate was 17.2% (23/134), with the median age of death between 24 gestational weeks in fetuses and 1-month-old in infants. Respiratory failure was the leading cause of death in live-born patients (58.8%, 10/17), especially during the neonatal period. Our findings expanded the genotype and phenotype spectrum of neonatal SYS patients. The results demonstrated that respiratory dysfunction was a typical characteristic among Chinese SYS neonates that should attract physicians' attention. The early identification of such disorders allows early intervention and can further provide genetic counseling as well as reproductive options for the affected families.

PEBAT, an Intriguing Neurodegenerative Tubulinopathy Caused by a Novel Homozygous Variant in TBCD: A Case Series and Literature Review

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course.

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Atypical hemolytic uremic syndrome induced by SARS-CoV2 infection in infants with EXOSC3 mutation.

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy mainly in the kidneys and mostly due to genetic disorders leading to uncontrolled activation of the complement system. Severe complications of SARS-CoV2 infection are linked to microvascular injury and complement activation is suspected to play a role in the pathogenesis of endothelial cell damage in severe COVID-19.MethodsWe present the first two cases of aHUS triggered by SARS-CoV-2 infection in two unrelated infants with the same mutation in the RNA exosome gene EXOSC3. This mutation is known to cause pontocerebellar hypoplasia type 1b, an autosomal-recessive neurodegenerative disease. So far, no kidney involvement in affected persons was reported.ResultsAs eculizumab treatment was unsuccessful and complement-mediated disorders were ruled out, we suppose that the atypical HUS in our two patients is not due to complement-mediated thrombotic microangiopathy but rather due to a dysfunction of the RNA exosome.ConclusionsThe RNA exosome is crucial for the precise processing and degradation of nuclear and cytoplasmatic RNA. We suspect that the SARS-CoV-2 infection led to changes in RNA that could not be offset by the defective RNA exosome in our two patients. The accumulation/wrong processing of the viral RNA must have led to the endothelial cell damage resulting in aHUS. This would be a new — “RNA-induced” — mechanism of aHUS.

Longitudinal gut virome analysis identifies specific viral signatures that precede necrotizing enterocolitis onset in preterm infants

Necrotizing enterocolitis (NEC) is a serious consequence of preterm birth and is often associated with gut bacterial microbiome alterations. However, little is known about the development of the gut virome in preterm infants, or its role in NEC. Here, using metagenomic sequencing, we characterized the DNA gut virome of 9 preterm infants who developed NEC and 14 gestational age-matched preterm infants who did not. Infants were sampled longitudinally before NEC onset over the first 11 weeks of life. We observed substantial interindividual variation in the gut virome between unrelated preterm infants, while intraindividual variation over time was significantly less. We identified viral and bacterial signatures in the gut that preceded NEC onset. Specifically, we observed a convergence towards reduced viral beta diversity over the 10 d before NEC onset, which was driven by specific viral signatures and accompanied by specific viral-bacterial interactions. Our results indicate that bacterial and viral perturbations precede the sudden onset of NEC. These findings suggest that early life virome signatures in preterm infants may be implicated in NEC.

Molecular study of infantile Spinal Muscular Atrophy

Infantile Spinal Muscular Atrophy (SMA) is a group of autosomal recessive disorders characterized by a degeneration of the motor neurons in the anterior horn of the spinal cord leading to a progressive paralysis of the limbs and trunk with muscle atrophy. 95% of cases are due to exon 7 deletions in the SMN gene. The aim of this work is to determine the frequency of the exon 7 deletion in the SMN1 gene in congenital hypotonia of unknown cause in some Moroccan patients.
 The exon 7 deletion of the SMN1 gene was investigated in 29 unrelated Moroccan infants. These patients were referred to the genetic consultation for congenital hypotonia during the period from June 2013 to June 2021. The identification of exon 7 deletion was performed using PCR-RFLP. Homozygous deletion was found in 15 infants (52%) while 14 patients had negative results. On the other hand, deletions of NAIP gene and exon 8 of the SMN gene are in progress.
 The 5q13 region (SMA locus) is composed of two 500 kb elements, duplicated and inverted, each element containing one copy of the SMN gene, one copy of the NAIP gene and one copy of the p44 gene. Deletions of exon 7 of the SMN1 gene cause the accumulation of the abnormal SMN protein and consequently its absence in axonal extensions. Thereby, the identification of this mutation remains important in infants with congenital hypotonia without obvious cause. This easy genetic test should be systematically proposed after a well-established genetic counseling.
 Keywords: SMN, SMA, Congenital hypotonia, NAIP.

Heterozygous missense variant of the proteasome subunit \u03b2-type 9 causes neonatal-onset autoinflammation and immunodeficiency

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.

Male care in a free-ranging group of Japanese macaques (Macaca fuscata).

Among the Macaca species, adult male Japanese macaques are the least likely to perform male care (i.e., affiliative interactions between adult males and immatures, including holding, carrying, and grooming); however, they perform male care for infants, albeit infrequently. We examined 17 cases of male care observed for the first time when the immature was younger than 1year of age. Eleven of the 31 adult males who remained as central males during the 30-year observation period performed male care. Their age and dominance rank did not influence the occurrence of male care. Most cases were first recorded between the last part of the mating season and the first part of the birth season (January-March), whereas male care was rarely observed during the mating season (October-December). In 12 of the 17 cases, male care ceased within 6months after the first observation, whereas in the remaining cases, it continued for at least 1year. In 15 of the 17 cases, males tended to perform male care for matrilineally unrelated female infants of low-ranking mothers. In some cases, the male and infant mother showed grooming interactions for 6months both before and after the start of male care, whereas such grooming interactions were never recorded either before or after the start of male care in other cases. We also examined some hypotheses on male-immature associations and the probable benefits that males and infants might acquire through male care.

Sex Differences in Gut Microbial Development of Preterm Infant Twins in Early Life: A Longitudinal Analysis.

Infant gut microbiota plays a vital role in immune response, mediates neurobehavioral development and health maintenance. Studies of twins’ gut microbiota found that gut microbiota composition and diversity tend to be mature and stable with increasing postnatal age (PNA). Preterm infant gut microbiome shifts dramatically when they were staying in the neonatal intensive care unit (NICU). Compositions and shifting characteristics of gut microbiota among neonatal preterm twins and triplets during their early life are still unknown, which impedes a better understanding of the mechanism underpinning neurobehavioral development and precise intervention/health of preterm neonates. This longitudinal cohort study used a twins/triplets design to investigate the interaction of genetic (e.g., male vs. female) and environmental factors influencing the development of the gut microbiome in early life. We included 39 preterm infants, 12 were Female twins/triplets (Female T/T) including 3 twins pairs and 2 triplets, 12 were male twins (Male T) including 6 twins pairs, and 15 were mixed-sex twins/triplets (Mix T/T) including 6 twins pairs and 1 triplet (8 females and 7 males) during the first four weeks of NICU stay. Weekly gut microbiota patterns between females and males were compared by linear discriminant analysis (LDA) effect size (LEfSe). Metagenomics function of gut microbiota was predicted by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Weekly function (KEGG pathways) differences between females and males were detected by using Statistical Analysis of Metagenomic Profiles (STAMP). Results found that female pairs and male pairs were significantly different in gut microbiome diversity, compositions, and predicted metabolic profiles, importantly, females and males were also significantly dissimilar within their co-twin/triplet pairs of the mixed-sex group, infants of co-twins/triplets shared more similar features than un-related infants from different twins’ pair. Future research developing personalized interventions for vulnerable high-risk infants should consider sex, and the interaction of sex and environmental factors.

InStrain profiles population microdiversity from metagenomic data and sensitively detects shared microbial strains.

Coexisting microbial cells of the same species often exhibit genetic variation that can affect phenotypes ranging from nutrient preference to pathogenicity. Here we present inStrain, a program that uses metagenomic paired reads to profile intra-population genetic diversity (microdiversity) across whole genomes and compares microbial populations in a microdiversity-aware manner, greatly increasing the accuracy of genomic comparisons when benchmarked against existing methods. We use inStrain to profile >1,000 fecal metagenomes from newborn premature infants and find that siblings share significantly more strains than unrelated infants, although identical twins share no more strains than fraternal siblings. Infants born by cesarean section harbor Klebsiella with significantly higher nucleotide diversity than infants delivered vaginally, potentially reflecting acquisition from hospital rather than maternal microbiomes. Genomic loci that show diversity in individual infants include variants found between other infants, possibly reflecting inoculation from diverse hospital-associated sources. inStrain can be applied to any metagenomic dataset for microdiversity analysis and rigorous strain comparison.

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5–14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.

When will the Bruce effect evolve? The roles of infanticide, feticide and maternal death

In many mammalian species, males are selected to kill unrelated infants and/or fetuses in order to cause lactating and pregnant females to begin cycling sooner than they otherwise would. As a result, females have evolved numerous counterstrategies to prevent infanticide and feticide. One such proposed counterstrategy is the Bruce effect, an apparently costly strategy in which inseminated or pregnant females cease reproductive investment in a developing embryo or fetus following exposure to nonsire males. Here I present a quantitative model that seeks to explain under what conditions females will be selected to exhibit the Bruce effect (i.e. to block or terminate pregnancy) rather than risking future infanticide or feticide. I first present an analytical model of the costs of the Bruce effect relative to the costs of potential feticide or infanticide. I then test the resulting predictions using an individual-based model operating under ecologically relevant conditions. The individual-based model predicts that moderate and high, but not low, levels of infanticide can produce selection for the Bruce effect. In contrast, feticide risk alone is unlikely to lead to selection for the Bruce effect, although feticide risk coupled with a substantial risk of female mortality following feticidal attack can. The model correctly predicts the evolution of the Bruce effect in geladas, Theropithecus gelada, and correctly predicts the absence of a Bruce effect in chacma baboons, Papio ursinus, and yellow baboons, Papio cynocephalus. Finally, I present a framework by which researchers can predict whether they expect to find infanticide, feticide and/or the Bruce effect in their study species.

Discordant transmission of bacteria and viruses from mothers to babies at birth

BackgroundThe earliest microbial colonizers of the human gut can have life-long consequences for their hosts. Precisely how the neonatal gut bacterial microbiome and virome are initially populated is not well understood. To better understand how the maternal gut microbiome influences acquisition of the infant gut microbiome, we studied the early life bacterial microbiomes and viromes of 28 infant twin pairs and their mothers.ResultsInfant bacterial and viral communities more closely resemble those of their related co-twin than unrelated infants. We found that 63% of an infant’s bacterial microbiome can be traced to their mother’s gut microbiota. In contrast, only 15% of their viral communities are acquired from their mother. Delivery route did not determine how much of the bacterial microbiome or virome was shared from mother to infant. However, bacteria-bacteriophage interactions were altered by delivery route.ConclusionsThe maternal gut microbiome significantly influences infant gut microbiome acquisition. Vertical transmission of the bacterial microbiome is substantially higher compared to vertical transmission of the virome. However, the degree of similarity between the maternal and infant gut bacterial microbiome and virome did not vary by delivery route. The greater similarity of the bacterial microbiome and virome between twin pairs than unrelated twins may reflect a shared environmental exposure. Thus, differences of the inter-generation transmissibility at birth between the major kingdoms of microbes indicate that the foundation of these microbial communities are shaped by different rules.3nSue88y6BfvksFidvuVsSVideo

AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases

Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 -2016, three had ∆4-3-oxosteroid 5β-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5β-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population.