Asymptomatic Mother Research Articles

A unique case of neurodevelopmental disorders and epilepsy linked to WDR45 variant inheritance and maternal mosaicism

This paper reports a case of a WDR45 variant inherited from an asymptomatic low-percentage mosaic mother. The proband boy was found to have significant psychomotor developmental delay, epilepsy, and abnormal liver function at four months of age, and a hemizygous variant WDR45 c.867_869dupGTA (p.Y290*) was detected by high throughput sequencing, which has an ACMG rating of likely pathogenic variant. The same variant was detected by high-throughput sequencing of the amniotic fluid of the fetus at his mother’s next pregnancy. Eventually, the same variant was detected in mosaic status in the unaffected mother by target capture-based deep sequencing of the asymptomatic mother, with a mutation load of 4.06 %.

Optical genome mapping reveals maternal mosaicism in two Sibling cases of Early-Onset Facioscapulohumeral muscular dystrophy type 1

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition caused by shortened D4Z4 repeat units in the subtelomeric region of 4q35, always on the 4qA haplotype, or due to variants in the SMCHD1 gene leading to hypomethylation of the D4Z4 macrosatellite DNA repeats. MethodsTo explore the potential genetic basis for suspected FSHD presenting with early onset in two siblings without evident family history of the disorder, whole genome sequencing (WGS) and optical genome mapping (OGM) were conducted on the affected individuals and their parents. ResultsThe two siblings manifested severe and early-onset clinical features consistent with FSHD, initiating with facial muscle weakness that progressively spread downward since the age of four months. OGM disclosed a reduced number of D4Z4 repeat units within the subtelomeric region of 4q35 in both affected siblings. This finding was pivotal in establishing the diagnosis of FSHD1 in the two brothers. The analysis also revealed that their clinically asymptomatic mother harbored the pathogenic D4Z4 repeat configuration (4qA) at a 50% frequency, indicating her mosaic carrier status. Additionally, WGS and Sanger sequencing identified a paternal origin variant c.695_699del (p.Val232Glyfs*7) in the DNAJB6 gene in both siblings. ConclusionThe application of advanced genomic methodologies has proven instrumental in unraveling the intricacies of genetic diseases that challenge traditional diagnostic paradigms. Specifically, this study highlights the effectiveness of OGM in diagnosing FSHD1 and confirming D4Z4 repeat reduction, particularly in cases involving parental mosaicism.

Molecular and Clinical Heterogeneity in Hungarian Patients with Treacher Collins Syndrome-Identification of Two Novel Mutations by Next-Generation Sequencing.

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder with variable penetrance and high genetic and phenotypic heterogeneity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, and POLR1B genes, and its major characteristic features are malar and mandibular hypoplasia, downward slanting of the palpebral fissures, and conductive hearing loss. In this study, five patients (two males and three females, age range from 2 to 29 years) with TCS were tested by Next-Generation Sequencing (NGS)-based sequencing and clinically characterized. Genetic analyses detected two deletions and one insertion in the TCOF1 gene and one missense variant in the POLR1D gene. Two novel mutations, c.1371_1372insT (p.Lys458*) in the TCOF1 gene and c.295 G>C (p.Gly99Arg) in the POLR1D gene, were identified. Moreover, two already known mutations, c.4369_4373del (p.Lys1457Glufs*12) and c.2103_2106del (p.Ser701Argfs*9) in the TCOF1 gene, were detected. The novel TCOF1 c.1371_1372insT mutation was associated with mild craniofacial manifestations and very rare symptoms of TCS, i.e., developmental delay and moderate intellectual disability. Although incomplete penetrance is a known phenomenon in TCS, surprisingly, the majority of our patients inherited the disease-causing variants from an asymptomatic mother. The unique feature of our study is the observation of causative mutation transmission between asymptomatic family members. Our results expanded the clinical and mutational spectrum of TCS and further confirmed the inter- and intra-familial variability of this disorder.

Hypermagnesemia-induced pseudonecrotizing enterocolitis and respiratory distress in a preterm infant: A case report

Rationale: This case highlights the rare yet critical diagnosis of hypermagnesemia in a preterm infant, who presented with symptoms mimicking necrotizing enterocolitis. It underscores the importance of considering hypermagnesemia as a differential diagnosis in neonatal respiratory distress and gastrointestinal symptoms, even when the cause is not immediately apparent. Patient’s Concern: An extremely low birth infant with respiratory distress further had episodes of apnoea and cyanosis. The infant eventually exhibited abdominal distension and bilious vomiting, symptoms mimicking necrotizing enterocolitis. Diagnosis: The infant’s clinical features were attributed to hypermagnesemia, despite no magnesium being administered and no apparent cause identified. Screening the apparently asymptomatic mother confirmed a serum magnesium level of 4 mg/dL, suggesting transplacental transfer as the likely cause of the neonate’s condition. Interventions: The newborn was treated supportively with adequate hydration and maintenance calcium gluconate. Outcomes: Magnesium levels decreased, and the baby showed signs of improvement. Lessons: Hypermagnesemia, though uncommon, should be investigated and considered even when the symptoms are not apparent.

Genetic analysis of a child with Hereditary hemorrhagic telangiectasia type I in conjunct with Splenic sinus shore cell hemangioma

To explore the genetic basis and pathogenesis for a child with type I Hereditary hemorrhagic telangiectasia (HHTⅠ) and Splenic sinus shore cell hemangioma (LCA). A child with HHT complicated with LCA diagnosed at the First Affiliated Hospital of Dali University in April 2022 was selected as the study subject. Clinical data of the child and her relatives were collected, and pathogenic variants were screened by whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. The patient, a 16-year-old female, had recurrent epitaxis since childhood, which sometimes necessitated hemostasis treatment. She also had splenectomy due to splenic rupture and was diagnosed with LCA. Her father and grandmother also had a history of recurrent epitaxis. Her father had deceased due to cerebral vascular rupture. The child was found to harbor a c.360+1G>A variant in the ENG gene. The same variant was not found in her asymptomatic mother and brother. The c.360+1G>A variant of the ENG gene probably underlay the pathogenesis in this child.

NGS-Based Identification of Two Novel PCDH19 Mutations in Female Patients with Early-Onset Epilepsy.

Developmental and epileptic encephalopathy-9 (DEE9) is characterized by seizure onset in infancy, mild to severe intellectual impairment, and psychiatric features and is caused by a mutation in the PCDH19 gene on chromosome Xq22. The rare, unusual X-linked type of disorder affects heterozygous females and mosaic males; transmitting males are unaffected. In our study, 165 patients with epilepsy were tested by Next Generation Sequencing (NGS)-based panel and exome sequencing using Illumina technology. PCDH19 screening identified three point mutations, one indel, and one 29 bp-long deletion in five unrelated female probands. Two novel mutations, c.1152_1180del (p.Gln385Serfs*6) and c.830_831delinsAA (p.Phe277*), were identified and found to be de novo pathogenic. Moreover, among the three inherited mutations, two originated from asymptomatic mothers and one from an affected father. The PCDH19 c.1682C>T and c.1711G>T mutations were present in the DNA samples of asymptomatic mothers. After targeted parental testing, X chromosome inactivation tests and Sanger sequencing were carried out for mosaicism examination on maternal saliva samples in the two asymptomatic PCDH19 mutation carrier subjects. Tissue mosaicism and X-inactivation tests were negative. Our results support the opportunity for reduced penetrance in DEE9 and contribute to expanding the genotype-phenotype spectrum of PCDH19-related epilepsy.

Improving Diagnostic Precision: Phenotype-Driven Analysis Uncovers a Maternal Mosaicism in an Individual with RYR1-Congenital Myopathy.

Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.

Asymptomatic Congenital Parvovirus infection in a neonate born to an asymptomatic mother with Parvovirus infection in the third trimester - Management issues

Asymptomatic Congenital Parvovirus infection in a neonate born to an asymptomatic mother with Parvovirus infection in the third trimester - Management issues

Enhanced fetal hematopoiesis in response to symptomatic SARS-CoV-2 infection during pregnancy

BackgroundPregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation.MethodsWe studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2.ResultsHere we show that symptomatic maternal COVID-19 is associated with a transcriptional erythroid cell signature as compared with asymptomatic and uninfected mothers. We observe an expansion of fetal hematopoietic multipotent progenitors skewed towards erythroid differentiation that display increased clonogenicity. There was no difference in inflammatory cytokines levels in the cord blood upon maternal SARS-CoV-2 infection. Interestingly, we show an activation of hypoxia pathway in cord blood cells from symptomatic COVID-19 mothers, suggesting that maternal hypoxia may be triggering this fetal stress hematopoiesis.ConclusionsOverall, these results show a fetal hematopoietic response to symptomatic COVID-19 in pregnant mothers in the absence of vertically transmitted SARS-CoV-2 infection which is likely to be a mechanism of fetal adaptation to the maternal infection and reduced oxygen supply.

Female Hemophilia in a Set of Triplets

Female Hemophilia In A Set Of Triplets Introduction: Hemophilia A (HA) and B (HB) are the most common inherited bleeding disorders. Gene sequencing identifies specific mutations and their associations with plasma factor levels and clinical phenotypes. Both HA and HB are X-linked recessive disorders, where the female carriers pass the gene onto their descendants. Males who inherit the mutated gene from their mothers develop the disease, whereas females are carriers due to having one normal gene, they typically do not display the characteristic features of hemophilia and have moderately low factor VIII levels of less than 40%. Female carriers may have bleeding symptoms, yet they do not experience as severe morbidities as the male hemophilia patients, due to having higher plasma factor VIII levels. Rarely female carriers can be severely affected and may have plasma factor VIII activities comparable to those with severe hemophilia. Here we are presenting a set of triplets, where the male infant and one of his sisters have severe hemophilia while the other sister is a hemophilia carrier. Methods: A set of triplets a male and two female neonates were born after 33 weeks of gestation to a healthy mother. Female neonates were dichorionic but shared the same placenta. The male infant had a circumcision at six weeks of age, which was complicated with prolonged bleeding. He was brought to the hospital and was diagnosed with severe HA. (Table.1). Infant #2 was admitted to the hospital for skin rash at age 8 weeks. She had staphylococcal scalded skin syndrome and was treated with vancomycin and cephalexin. She was noted to have prolonged bleeding from needle puncture sites. She was diagnosed with severe HA. The bleeding was controlled with tight packing. After a week of treatment her rash cleared, and she was discharged home. (Table 1). Infant #3 She was a healthy baby with no bleeding problems. (Table 1). Results and conclusions: We presented three infant-triplets-with factor VIII deficiency; infant #1 and infant #2 have severe HA. Infant #3 is an asymptomatic carrier. They all have the same mutation as their asymptomatic carrier mother. Infant #1 the male infant developed severe HA due to having the hemophilia allele on his “X” chromosome. Infant #3 a female infant is an asymptomatic carrier. She inherited the hemophilia allele on the X chromosome from her carrier mother and has an X chromosome bearing the normal allele, thus is able to produce factor VIII of 40%. Infant #2 the other female infant had severe HA, with a factor VIII activity of <0.3%. Female hemophilia is rare occurrence. Hemophilia treatment center (HTT) population profile (PP) reported that of the 1,676 females attending to HTC, 47.6% of them had less than 40% factor level, 0.48% of them had severe, 1.4% had moderate and 17.9% had mild hemophilia[Haemophilia. 2021:27(6):1037-1044. Doi:10.1111}. This can occur, in the setting of monosomy X (Turner syndrome-XO), due to having one X chromosome carrying the hemophilic gene or in the setting of compound heterozygosity: the female product of a father with hemophilia and the mother being a carrier. Similarly, hemizygosity of the hemophilic gene on both parents would result in hemophilia in their daughters. Another mechanism that plays a role in the pathogenesis of female hemophilia is the “X chromosome inactivation (XCI). This has been described as the most common cause of female hemophilia. One of the two X chromosomes in females is randomly and permanently inactivated in cells to ensure the balance with one X chromosome of males and limit the overproduction of potentially toxic gene proteins. The degree of inactivation determines the plasma levels of the gene products, in hemophilia the factor levels. The chromosome analysis of infant #2 revealed normal 46XX. Structural chromosomal abnormality is ruled out as she did not have Turner syndrome “XO”, or “45XY” with androgen insensitivity syndrome, nor did she have compound heterozygosity or hemizygosity of the X chromosome. The father had normal coagulation studies and factor VIII activity. Therefore, we believe infant #2 had extremely skewed XCI and the inactivation is skewed in favor of hemophilic X chromosome. This mechanism resulted in severe HA in this infant. The infants are now seven months old and have no bleeding problems, as infant #1 and #2 are on prophylaxis with emicizumab (Hemlibra), they both have 1% factor activity by chromogenic assay and do not have inhibitors. (Table 1)

IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia.

Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early regression. In parallel, inherited IRF2BPL variants have been reported in cohorts of patients with late-onset progressive dystonic and ataxic syndrome with few information about the neurodevelopment of these patients. This study aimed to describe both neurodevelopmental and neurodegenerative aspects of the phenotype in adults with IRF2BPL pathogenic variant. We report here the clinical and molecular data of 18 individuals carrying truncating IRF2BPL variants (identified by either exome or genome sequencing), including a large pedigree of 16 patients presenting with a neurodevelopmental disorder (NDD) associated with late-onset cerebellar ataxia and atrophy. Genome sequencing identified the p.(Gln117*) variant in a large family first assessed for familial ataxia, with multiple individuals presenting with NDD. The p.(Ser313*) variant was identified by exome sequencing in a second family with a young adult patient with NDD without ataxia which was inherited from her asymptomatic mother, suggesting incomplete penetrance of IRF2BPL-linked disorders. This study illustrates the importance of neurologic evaluation of adult patients initially diagnosed with NDD to detect a late-onset neurodegenerative condition. Two different disorders may be clinically diagnosed in the same family, when not considering that NDD and late cerebellar changes may be part of the same molecular spectrum such as for IRF2BPL.

SAT491 Development of Thyroidal Nodule in Congenital Hypothyroid Girl With Thyroid Peroxidase Gene Mutation

Abstract Disclosure: J. Lee: None. A. Oh: None. H. Han: None. Background: Reduced thyroxine synthesis in dyshormonogenesis induces increased thyrotropin (TSH) secretion through reduced negative feedback of thyroxine. Consequently, the affected patients are born with goiter or develop postnatal goiter, when L-thyroxine (LT4) supplementation is delayed. Cases of thyroid cancer have been reported in congenital hypothyroidism (CH) due to dyshormonogenesis, usually of follicular histology. Clinical Case: A 22-year lady has been taking LT4 since 8-years, under the diagnosis of goitrous CH. Her mother recalled neck swelling at newborn period. However, normal newborn screening test prevented neonatal goiter from further investigation. Initial test at 8-year of age revealed normal thyroid function without thyroid auto-antibodies, diffuse enlarged thyroid gland with increased uptake on 99mTc scan, and diffuse thyroid enlargement with heterogeneous echogenicity on ultrasonography (US). The goiter size waxed and waned according to the drug compliance. The highest TSH level (normal 0.17-4.05 μIU/mL) was 8.68 μIU/mL even without medication for 8 months by her own judgement. At 11.5-years, US found isoechoic solid nodule of 1.8 x 1.7 x 1.6 cm with peripheral halo in the inferior aspect of right thyroid, which was demonstrated to be benign follicular lesion favoring nodular hyperplasia on fine needle aspiration biopsy. With good drug compliance, the nodule size decreased to 1.1 x 0.9 cm at 18-years, and peripheral calcification appeared around the isoechoic solid nodule previously reported without change in size at 22-years. NGS panel for CH reported compound heterozygous variants in TPO gene. One pathogenic variant from asymptomatic father is c.2757del;p.(Met921Trpfs*53), the other likely pathogenic variant from asymptomatic mother is c.1580G>T;p.(Trp527Leu). Conclusion: This case is demonstrating development of thyroid nodule even with mild increased TSH level during LT4 medication in dyshormonogenic CH caused by TPO mutation. Regular follow-up and compliance to LT4 might be important to avoid thyroid tissue stimulation and possibly nodule formation by elevated TSH. Presentation Date: Saturday, June 17, 2023

Prenatal transmission of severe acute respiratory syndrome coronavirus 2, resulting in neonatal severe acute pneumonia, from an asymptomatic mother: a case report

BackgroundWe report a case of prenatal coronavirus disease 2019, which evolved 6 days after birth into severe pneumonia with signs of multiple organ failure, in a mother with asymptomatic coronavirus disease 2019.Case presentationAt minute 11 of life, our patient from Afro-Caribbean had polypnea with mild signs of struggle; Silverman’s index was scored at three. Chest radiography showed bilateral opacities consistent with respiratory distress syndrome. On the 6th day of life, a thoracic computed tomography scan showed bilateral parenchymatous lesions (10–20%) in ground glass, compatible with coronavirus disease 2019-type infection. At the same time, the neonate showed signs of multiple organ failure (elevated liver and cardiac enzyme levels). She was treated with azithromycin (20 mg/kg/day) for 5 days. All the signs recovered fully by day 12. Real-time polymerase chain reaction results were positive in the first 30 min of life, suggesting prenatal transmission. Our patient has been followed until 2 years old and is developing well with no sequelae.ConclusionThis case report demonstrates the incompatibility between maternal asymptomatic coronavirus disease 2019 and severe neonatal lung involvement. We emphasize the need for vigilance to avoid missing the most severe forms of neonatal coronavirus disease 2019.

Is there a reactive IgG antibody for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in maternal breast milk?

Restricted data on the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reactive IgG antibodies by breast milk to infants, born to mothers who did not know if they had coronavirus disease 2019 (COVID-19), are presented. The objective of the present work was to demonstrate the existence of specific IgG antibodies against the SARS‐CoV‐2 virus in the milk of breastfeeding mothers in the suburban area of Şanlıurfa, Türkiye. This retrospective analysis examined the medical records of maternal and neonatal data for all 51 newborns to 50 mothers from September to October 2020. The present work was approved by the local medical ethics committee. Written informed consent was obtained from the mothers. Testing SARS-CoV-2 reactive IgG was performed using ELISA assay. SARS-CoV-2 reactive IgG were detected in 58% of breast milk. Over the past year, SARS-CoV-2 reactive IgG identified in breast milk of mothers without symptoms of viral respiratory infection (self-reported diagnosis) was 12.5 times lower than mothers with symptoms. The IgG responses were different between symptomatic and asymptomatic mothers’ and infants’ samples. These results propose that along with the COVID-19 pandemic, breastfeeding could be safe, and the existence of SARS-CoV-2-reactive IgG antibodies in breast milk could provide passive immunity to breastfed infants, and keep them safe against COVID-19 infection.

Maternal and neonatal COVID-19 – the pandemic experience in a tertiary maternity unit in Romania – unicentric, prospective study

Background and objectives. Multiple reports, available while the pandemic progressed, raised concerns that COVID-19 poses higher risks to pregnant women and their newborns. Still, limited evidence exists on the impact of the COVID-19 pandemic during pregnancy and perinatal period. This study aimed to evaluate the rate of early-onset neonatal COVID and the outcomes of newborns born by mothers diagnosed with COVID-19 at delivery and concerning the presence of maternal symptoms and dominant SARS-CoV-2 variant. Materials and methods. The prospective study of maternal and neonatal data of mothers with confirmed SARS-CoV-2 infection at admission for delivery and their newborns was developed in a tertiary maternity hospital between February 1, 2020, and December 1, 2023. All pregnant women admitted for delivery were screened for the presence of SARS-CoV-2 infection, and, if positive, the newborn was also screened. Data of all pregnant women with positive RT-PCT test and of their newborns were extracted from the maternal and neonatal medical charts and the electronic data system of the hospital: data on pregnancy, delivery, COVID-19 symptoms, demographics, gestational age, birth weight, Apgar score, neonatal pathology, and routine laboratory tests, results of maternal and neonatal RT-PCR for SARS-CoV-2 virus, feedings, and death were extracted from the neonatal charts. The primary outcomes were neonatal: COVID-19 rates, prematurity, birth weight, symptoms, and neonatal conditions. IBM SPSS 23 was used for data analysis and comparisons. Results. A total number of 218 mothers with COVID-19 infection (92.7% asymptomatic) and their 218 neonates were included in the study. COVID-19 infection occurred in 1.91% of the deliveries registered in the unit during the study period. Neonatal COVID-19 was diagnosed in 3/218 infants, none symptomatic, with a rate of transmission of 1.37%. Most of the newborns delivered by COVID-19-positive mothers were born at term, only 14 were born prematurely, and 16 had birth weight <2500 g; 15% of the newborns delivered by COVID-19-infected mothers had a neonatal condition that needed significant interventions or therapies. The mean gestational age and Apgar score at 1 minute were significantly lower in infants delivered by symptomatic mothers and during the Delta/Omicron/other new variants period as compared to those born by asymptomatic mothers or during the pre-Delta period, respectively. Also, major and minor neonatal conditions were found more often in infants delivered by symptomatic mothers (p<0.050) and in those born during the Delta/Omicron/other new variants period (p<0.050). Conclusions. Our study found low rates of maternal COVID-19 at admission for delivery, and symptomatic maternal COVID-19. Also, we have found low rates of prematurity and LBW, in hospital maternal-neonatal transmission of SARSCoV-2, and excellent neonatal outcomes among the infants delivered by SARS-CoV-2 mothers, although gestational age and perinatal complications were more frequent in infants born by symptomatic mothers and during Delta/Omicron/ other new SARS-CoV-2 variants period. More studies are needed to completely reveal the impact of the virus on fetal, neonatal, infant, and child growth, health, and development.

Identification and characterization of the largest deletion in the PCCA gene causing severe acute early-onset form of propionic acidemia.

Whole-exome sequencing (WES) is an excellent method for the diagnosis of diseases of uncertain or heterogeneous genetic origin. However, it has limitations for detecting structural variations such as InDels, which the bioinformatics analyzers must be aware of. This study aimed at using WES to evaluate the genetic cause of the metabolic crisis in a 3-day-old neonate admitted to the neonatal intensive care unit (NICU) and deceased after a few days. Tandem mass spectrometry (MS/MS) showed a significant increase in propionyl carnitine (C3), proposing methylmalonic acidemia (MMA) or propionic acidemia (PA). WES demonstrated a homozygous missense variant in exon 4 of the BTD gene (NM_000060.4(BTD):c.1330G > C), responsible for partial biotinidase deficiency. Segregation analysis of the BTD variant revealed the homozygous status of the asymptomatic mother. Furthermore, observation of the bam file, around genes responsible for PA or MMA, by Integrative Genomics Viewer (IGV) software displayed a homozygous large deletion in thePCCAgene. Comprehensive confirmatory studies identified and segregated a novel outframe deletion of 217,877bp length, "NG_008768.1:g.185211_403087delinsTA", extended from intron 11 to 21 of the PCCA, inducing a premature termination codon and activation of nonsense-mediated mRNA decay (NMD). Homology modeling of the mutant PCCA demonstrated eliminating the protein's active site and critical functional domains. Thereupon, this novel variant is suggested as the largest deletion in the PCCA gene, causing an acute early-onset PA. These results could expand the PCCA variants spectrum, and improve the existing knowledge on the molecular basis of PA, as well as provide new evidence of pathogenicity of the variant (NM_000060.4(BTD):c.1330G > C.

Abstract A51: Divergent effects of MDS predisposing SAMD9L point mutations, in humans, mice, and cellular models

Abstract We previously showed that germline SAMD9 and SAMD9L (SAMD9/9L) disorders are the most common predisposition to childhood myelodysplastic syndromes with bone marrow failure (BMF). Heterozygous mutations in both genes are growth inhibitory and undergo negative selection by acquiring compensatory rescue events in blood. Here, we describe the first report of SAMD9L genetic rescue occurring during embryonal development and resulting in germline triple-allelic mosaicism (1 wildtype (WT) and 2 mutant alleles), where only one mutant allele was transmitted to each of the two diseased children. In a family of 2 affected siblings with hypocellular BMF, the Index case carried germline heterozygous SAMD9L V1512M mutation and her brother was heterozygous for V1512L mutation. The clinical presentation for Index with V1512M was more severe compared to her brother with V1512L mutation. Genetic assessment of the parents showed the asymptomatic mother to be a triple-allelic mosaic, carrying WT SAMD9L allele at ~50% frequency in all tissues, while both V1512M and V1512L mutant alleles “competed” in their allelic distribution depending on the tissue origin. Single-cell DNA sequencing on her peripheral blood (PB) revealed 3 independent diploid clones: V1512M in 14%, V1512L in 68%, and WT (due to revertant UPD7q) in 18% of cells. Because her parents were SAMD9L WT, one of the mutations likely arose de novo and underwent failed embryonic rescue attempt leading to a second mutation. Towards studying the effect on hematopoiesis in vitro, we knocked in V1512M and V1512L mutations in inducible pluripotent stem cells (iPSC). For in vivo functional validation, we created constitutive mouse models with ortholog mutations (V1507M and V1507L). Mutant hematopoietic progenitor cells from iPSC had severely compromised proliferative capacity and yielded fewer erythroid and myeloid cells. This effect was more severe in V1512M vs. V1512L mutants. The divergent mutational phenotypes were also replicated in our mouse models: two-thirds (13/19) of the heterozygous V1507M (V1507Mhet) pups died before 4 weeks of age. In contrast, V1507Lhet mice had overall survival equal to WT mice, while one-third of homozygous V1507L (V1507Lhom) mice showed decreased survival post 19 weeks of age. At baseline, V1507Mhet mice showed severe growth retardation with multisystemic issues, which were absent in the V1507L mutant models. PB cytopenia (anemia, B-cell lymphopenia) though observed in both V1507Mhet and V1507Lhom mice, the degree of severity was high in the V1507Mhet than in the V1507Lhom model. Meanwhile, V1507Lhet mice had blood counts similar to WT. In summary, V1512M compared to V1512L mutation resulted in a more severe phenotype in all analyzed model systems. This observation showed how different mutational permutations of the same amino acid can exert divergent phenotypic effects in SAMD9L BMF disorder. Therefore, together with our genetic analysis, we could postulate that the V1512L mutation arose as a failed rescue attempt of V1512M during embryogenesis. Citation Format: Sushree S Sahoo, Charnise Goodings, Shondra M. Pruett-Miller, Maria A Lillo, Lei Han, Baranda Hansen, Ti-Cheng Chang, Tim Lammens, Mattias Hofmans, Marta Derecka, Barbara De Moerloose, Marcin W Wlodarski. Divergent effects of MDS predisposing SAMD9L point mutations, in humans, mice, and cellular models [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A51.

Neurogenetics: Congenital Myotonic Dystrophy with asymptomatic mother may be missed by whole exome sequencing; Biopsy, DMPK1 gene testing and EMG may be required to resolve VUS in neonates, A Case report. (P6-8.010)

<h3>Objective:</h3> We show how biopsy, EMG, and <i>DMPK1</i> gene testing may be required for variant resolution. Whole exome sequencing revealed <i>NEB</i> (nebulin) (OMIM #161650) variants of uncertain significance inherited in <i>trans</i>. Muscle biopsy and EMG were helpful in resolving <i>NEB</i> VUS (variants of uncertain significance) and the detection of myotonia even as young as 6 days of age, with a clinically asymptomatic mother. <h3>Background:</h3> Myotonic dystrophy type 1 (myotonia dystrophia 1) is an autosomal dominant multisystem disorder caused by CTG expansion of the <i>DMPK1</i> gene (dystrophia myotonica protein kinase) (OMIM #605377) resulting in anticipation, whereby offspring have greater repeat expansion and severity. <h3>Design/Methods:</h3> <h3>Case Report:</h3> This full-term patient was born with severe hypotonia and respiratory depression. Brain MRI, EEG, Karyotype (46, XY) and FISH were normal. Whole Exome Sequencing (WES) revealed heterozygous <i>NEB</i> VUS, in <i>trans</i>, but histochemical and electron microscopic examinations of the muscle biopsy did not show nemaline rods. EMG was performed and revealed myotonic discharges. A genetic diagnosis of myotonic dystrophy type 1 was made, with over 200 CTG repeats in the <i>DMPK1</i> gene. A week after tracheostomy and g-tube placement, oxcarbazepine was trialed, after which he was able to be weaned off ventilation and discharged to home. He made substantial progress over the next year. <h3>Results:</h3> NA <h3>Conclusions:</h3> Neonatal muscle biopsies may not show nemaline rods due to being early or sampling error and thus further testing may be required. When evaluating severe congenital myopathies, testing for myotonic dystrophy should be considered. Myotonia may be found in neonates as young as 6 days old characterized as briefer duration with waning repetitive small amplitudes between 50–100uV without the classic sound on a spectrum with complex repetitive discharges. Severe congenital myotonic dystrophy patients may be born from an asymptomatic mother and the diagnosis may be missed by whole exome sequencing. <b>Disclosure:</b> Mr. Appiah has nothing to disclose. Dr. Shergelashvili has nothing to disclose. Dr. Marr has nothing to disclose. Ahmed Eldokla has nothing to disclose. Dr. LEBEL has nothing to disclose. Dr. Sakonju has nothing to disclose.

Prolonged Preterm Rupture of Membranes Associated with Neonatal Disseminated Herpes Simplex Virus Type 1 at Birth: Is There a Role for Preemptive Test and Treat Strategies in High-Risk Populations?

Neonatal herpes simplex virus (HSV) prevention focuses on mothers with prior or current genital disease [1]. However, primary asymptomatic maternal HSV-1 or HSV-2 cause most cases [2–5]. Prolonged membrane rupture is a major risk [6]. This newborn was born at 29 weeks after 14 days of ruptured membranes to an asymptomatic mother. No maternal HSV testing was performed. Vesicular lesions were present at birth with HSV DNA in skin, blood, and CSF; placental histology demonstrated viral particles (Figure 1). Primary maternal HSV-1 without protective antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies and limited placental antibody transfer were documented (Table 1) [7–10]. This case highlights the need for screening and preemptive treatment of high-risk subpopulations. Financial support. This work was supported by grants from National Institutes of Health, R01AI134367, R21AI147992, R01HD098977, and the Price Family Foundation. AMM is supported by Einstein-Montefiore CTSA training grant (TL1 TR002557).

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.