ABSTRACT
PURPOSE: Pregnancies complicated by prenatally suspected lower urinary tract obstruction (LUTO) can be associated with high rates of terminations due to potentially poor outcomes. Herein, we assessed autopsy findings of fetuses terminated for suspected LUTO to evaluate the prenatal diagnostic accuracy and spectrum of underlying pathologies. MATERIALS AND METHODS: We performed a retrospective review of all pregnancies referred to a high-risk fetal center in a universal access to care health care system for suspected LUTO that opted for termination of pregnancy between 2009 and 2022. Ultrasound features, genetic investigations, placental findings, and distribution of postmortem diagnoses were assessed. RESULTS: Of a total of 190 pregnancies with suspected LUTO evaluated during the study period, 79 (42%) were terminated. We excluded 35 fetuses with incomplete data, resulting in 44 available for analysis. Pregnancies were terminated at a mean gestation of 22 ± 5 weeks. A LUTO diagnosis was confirmed in 37 (84.1%) fetuses (35 males, 2 females), and the remaining 7 showed other pathologies. Pulmonary hypoplasia was found in 62.2% (n = 23) and placental pathologies in 56.8% of confirmed LUTO compared to 33.4% and 71.4% in non-LUTO cases, respectively. Overall, a total of 31 fetuses underwent additional prenatal investigations with genetic anomalies detected only in fetuses with a confirmed LUTO diagnosis (13.6%). CONCLUSIONS: In our health care system, almost half of prenatally suspected LUTO pregnancies are terminated. The sonographic diagnostic accuracy for LUTO is reasonable at 84%. However, the remaining 16% still had significant pathologies. Genetic abnormalities are uncommon and rarely the trigger for pregnancy terminations.
Subject(s)
Fetal Diseases , Urethral Diseases , Urethral Obstruction , Urinary Tract , Male , Pregnancy , Humans , Female , Fetal Diseases/diagnostic imaging , Fetal Diseases/genetics , Placenta , Fetus , Retrospective Studies , Ultrasonography, Prenatal/methodsABSTRACT
INTRODUCTION: Skeletal growth arrest lines (GAL) are transverse lines of metaphyseal radiodensity accompanying episodic severe physiological stress. They are poorly described in fetal remains. MATERIALS AND METHODS: We searched our autopsy practice for instances of fetal GAL in post mortem radiology, and correlated them with long bone histology and placental pathology. We describe the appearance, distribution, and pathology of GAL in a cohort of fetal autopsies, and compare the placental pathology accompanying GAL to the placental pathology of asymmetrical growth restriction (AGR) in the same time period. RESULTS: In 2108 consecutive fetal post mortems, we found 20 cases with GAL. About 16 were in singletons with AGR. In these 16, the distribution of placental pathologies was similar to a contemporaneous cohort of 113 cases with AGR. Of the remaining 4, two twins out of 9 sets of monochorionic twins with AGR demonstrated GAL. One case of GAL had symmetrical growth restriction with cytomegalovirus infection, and one case had no AGR and an old, unexplained retroplacental hemorrhage. On histology, GAL are characterized by a region of mineralized chondroid, which is variably incorporated into irregular trabecular bone. DISCUSSION: GALs accompany a variety of placental pathologies and twin-twin transfusion, suggesting episodic disease progression.
Subject(s)
Fetofetal Transfusion , Placenta , Pregnancy , Female , Humans , Placenta/pathology , Fetofetal Transfusion/pathology , Fetus/pathology , Fetal Growth Retardation/pathologyABSTRACT
Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis. Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo. c.1324 C > T; p.(Arg442*) is a nonsense variant resulting in protein truncation reported to be associated with RRS3. c.1366dup; p.(Leu456Profs*3) is a frameshift variant predicted to result in protein truncation reported to segregate with the disease in multiple affected individuals from a single large family with distal symphalangism of the fourth finger. Fetal autopsy following pregnancy termination showed a large head with low-set ears, facial abnormalities, mesomelic bone shortening, hemivertebra, fused S3 and S4 vertebral bodies, several fused rib heads and short penis with buried shaft.
Subject(s)
Dwarfism , Limb Deformities, Congenital , Receptor Tyrosine Kinase-like Orphan Receptors , Ultrasonography, Prenatal , Urogenital Abnormalities , Humans , Female , Pregnancy , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/diagnostic imaging , Adult , Spine/abnormalities , Spine/diagnostic imaging , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/diagnostic imaging , Fingers/abnormalities , Fingers/diagnostic imaging , Abnormalities, Multiple/genetics , Abnormalities, Multiple/diagnostic imaging , Male , Exome SequencingABSTRACT
OBJECTIVE: To describe the association between prenatal imaging and neurodevelopmental outcomes of fetuses with rhombencephalosynapsis (RES). STUDY DESIGN: Thirty-four pregnancies complicated by RES were identified from our institutional databases based on US and/or MRI findings. Genetic testing results were gathered. In cases of termination of pregnancy, we studied the association between prenatal imaging and neuropathologic findings. For those who opted for expectant management, comprehensive developmental assessments and postnatal MRI imaging were evaluated. RESULTS: Over one third of fetuses in our cohort had complete RES. Common intracranial anomalies identified were mesencephalosynapsis, aqueduct stenosis and diencephalosynapsis. The degree of RES was not associated with the frequency of additional central nervous system anomalies. MRI had a good correlation with neuropathologic findings with regard to the degree of RES, aqueduct stenosis and mesencephalosynapsis. Postmortem autopsy showed that one third of our cases had VACTERL-H and almost all of those had complete RES. All liveborn neonates(n = 6) had aqueduct stenosis requiring ventriculoperitoneal shunting within days of delivery (median 5 days). While a large proportion of prenatally suspected complete RES were found to have partial RES on postnatal imaging, prenatal diagnosis of aqueduct stenosis remained unchanged. All children that were at least 2 years old (n = 3) had global developmental delay. CONCLUSION: Prenatal assessment of the RES severity is challenging and may be unreliable. Nevertheless, postnatal prognosis is poor for both complete and partial RES. Associated aqueductal stenosis, can be reliably assessed prenatally and this may contribute to worse postnatal prognosis than the degree of RES.
ABSTRACT
INTRODUCTION: To determine lung hypoplasia in cases with fetal skeletal dysplasia based on the total lung weight at autopsy as the most accountable surrogate marker for pulmonary hypoplasia. METHODS: This retrospective cohort study included all pregnancies with antenatal diagnosis of skeletal dysplasia (2012-2018). We included only cases in which information on fetal biometry was available within 2 weeks before delivery and had autopsy and skeletal X-rays + molecular analysis using extracted fetal DNA. We compared the predictive accuracy of fetal sonographic body-proportional ratios (BPRs) including: (1) thoracic circumference-to-abdominal circumference ratio, (2) the femur length-to-abdominal circumference (FL/AC) ratio, (3) head circumference-to-abdominal circumference ratio, and (4) foot length-to-femur length ratio. Lung hypoplasia was defined as total lung weight below -2 SD from the expected mean for gestational age. RESULTS: Fifty three pregnancies with antenatal diagnosis of skeletal dysplasia underwent autopsy included. Lung hypoplasia was determined in 34 (64.1%). Median of gestational age at last sonographic assessment was 21.3 (19.9-24.9) weeks. FL/AC ratio demonstrated the highest area under the curve of 0.817 (95% CI: 0.685-0.949; p < 0.0001). FL/AC ≤0.1550 demonstrated the highest detection rate of 88.2% along with the highest negative predictive value of 75%. CONCLUSION: Using a novel, more practical approach to predict lung hypoplasia in skeletal dysplasia, fetal sonographic BPRs and, specifically, FL/AC ratio demonstrate a high detection rate of lung hypoplasia.
Subject(s)
Lung , Ultrasonography, Prenatal , Pregnancy , Humans , Female , Infant , Retrospective Studies , Lung/diagnostic imaging , Lung/abnormalities , Gestational Age , Fetal Weight , Fetus/diagnostic imagingABSTRACT
Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.
Subject(s)
Arthrogryposis , Pregnancy , Female , Humans , Arthrogryposis/diagnosis , Arthrogryposis/genetics , Prenatal Diagnosis , Homozygote , Prenatal Care , Syndrome , Connectin/geneticsABSTRACT
Exome sequencing is a powerful tool in prenatal and postnatal genetics and can help identify novel candidate genes critical to human development. We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32, including four fetal probands in three unrelated pedigrees and three pediatric probands in unrelated pedigrees. We also report clinical comparisons with seven previously published patients. Index probands were identified through an ongoing prenatal exome sequencing study and through an online data sharing platform (Gene Matcher™). A literature review was also completed. TBC1D32 is involved in the development and function of cilia and is expressed in the developing hypothalamus and pituitary gland. We provide additional data to expand the phenotype correlated with TBC1D32 variants, including a severe prenatal phenotype associated with life-limiting congenital anomalies.
Subject(s)
Ciliopathies , Pregnancy , Female , Humans , Child , Phenotype , Ciliopathies/diagnosis , Ciliopathies/genetics , Pedigree , Adaptor Proteins, Signal TransducingABSTRACT
Macrocephaly means a large head and is defined as a head circumference (HC) above the 98th percentile or greater than +2SD above the mean for gestational age. Macrocephaly can be primary and due to increased brain tissue (megalocephaly), which in most cases is familial and benign or secondary. The latter may be due to various causes, including but not limited to communicating or non-communicating hydrocephalus, cerebral edema, focal and pericerebral increased fluid collections, thickened calvarium and brain tumors. Megalocephaly can be syndromic or non-syndromic. In the former, gyral and structural CNS anomalies are common. It is important to exercise caution when considering a diagnosis of megalocephaly due to limitations in the accuracy of HC measurement, lack of nomograms for specific populations, inconsistencies between prenatal and postnatal HC growth curves and progression over time. The degree of macrocephaly is important, with mild macrocephaly ≤2.5SD carrying a good prognosis, especially when one of the parents has macrocephaly and normal development. Cases in which the patient history and/or physical exam are positive or when parental HC are normal are more worrisome and warrant a neurosonogram, fetal MRI and genetic testing to better delineate the underlying etiology and provide appropriate counseling.
Subject(s)
Megalencephaly , Prenatal Diagnosis , Pregnancy , Female , Humans , Megalencephaly/diagnosis , Megalencephaly/therapy , Genetic Testing , Gestational Age , Magnetic Resonance ImagingABSTRACT
OBJECTIVE: Genome sequencing (GS >30x) is beginning to be adopted as a comprehensive genome-wide test for the diagnosis of rare disease in the post-natal setting. Recent studies demonstrated the utility of exome sequencing (ES) in prenatal diagnosis, we investigate the potential benefits for GS to act as a comprehensive prenatal test for diagnosis of fetal abnormalities. METHODS: We performed GS on a prospective cohort of 37 singleton fetuses with ultrasound-identified structural abnormalities undergoing invasive prenatal testing. GS was performed in parallel with standard diagnostic testing, and the prioritized variants were classified according to ACMG guidelines and reviewed by a panel of board-certified laboratory and clinical geneticists. RESULTS: Diagnostic sequence variants were identified in 5 fetuses (14%), with pathogenic variants found in NIPBL, FOXF1, RERE, AMMECR1, and FLT4. A further 7 fetuses (19%) had variants of uncertain significance (VUS) that may explain the phenotypes. Importantly, GS also identified all pathogenic variants reported by clinical microarray (2 CNVs, 5%). CONCLUSION: Prenatal GS offered diagnoses (sequence variants and CNVs) in 19% of fetuses with structural anomalies. GS has the potential of replacing multiple consecutive tests, including microarray, gene panels, and WES, to provide the most comprehensive analysis in a timely manner necessary for prenatal diagnosis.
Subject(s)
Prenatal Diagnosis , Ultrasonography, Prenatal , Cell Cycle Proteins , Female , Fetus/diagnostic imaging , Humans , Pregnancy , Prospective Studies , Exome SequencingABSTRACT
Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary l -tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by a significant reduction in NAD levels via yeast genetic complementation assays. For the first time, missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder.
Subject(s)
NAD , Spine , Animals , Genotype , Humans , Mammals , Mutation, Missense , Spine/abnormalitiesABSTRACT
Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536-539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52-/- cells. Altogether, our findings allow a better comprehensive genotype-phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.
Subject(s)
Carrier Proteins/genetics , Centrosome/metabolism , Genetic Association Studies , Genetic Predisposition to Disease , Microtubules/metabolism , Mutation , Amino Acid Sequence , Animals , Animals, Genetically Modified , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Child , Child, Preschool , Cilia/metabolism , Consanguinity , DNA Mutational Analysis , Female , Genotype , Homozygote , Humans , Infant , Intracellular Signaling Peptides and Proteins , Male , Pedigree , Phenotype , Protein Binding , Protein Interaction Domains and Motifs/genetics , Trimethoprim, Sulfamethoxazole Drug Combination/metabolism , Exome Sequencing , ZebrafishABSTRACT
The National Kidney Registry (NKR) Advanced Donation Program enables living donors the opportunity to donate altruistically, or in advance of a potential recipient's transplant, and to receive a voucher that can be redeemed for a future transplant facilitated by the NKR. Family vouchers allow a donor to identify multiple individuals within their immediate family, with the first person in that group in need of a transplant being prioritized to receive a kidney. An increase in vouchers introduces concerns that demand for future voucher redemptions could exceed the supply of available donors and kidneys. A Monte Carlo simulation model was constructed to estimate the annual number of voucher redemptions relative to the number of kidneys available over a 50-year time horizon under several projected scenarios for growth of the program. In all simulated scenarios, the number of available kidneys exceeded voucher redemptions every year. While not able to account for all real-life scenarios, this simulation study found that the NKR should be able to satisfy the likely redemption of increasing numbers of vouchers under a range of possible scenarios over a 50-year time horizon. This modeling exercise suggests that a donor family's future needs can be satisfied through the voucher program.
Subject(s)
Kidney Transplantation , Tissue and Organ Procurement , Humans , Kidney , Living Donors , RegistriesABSTRACT
Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.
Subject(s)
Heart Defects, Congenital/genetics , Heart Valve Diseases/genetics , Receptor, Notch1/genetics , Bicuspid Aortic Valve Disease/genetics , Child, Preschool , Female , Gene Deletion , Haploinsufficiency/genetics , Heterozygote , Humans , Male , Pedigree , Penetrance , PregnancyABSTRACT
INTRODUCTION: Although fetal brain injury due to COL4A1 gene mutation is well documented, fetal central nervous system (CNS) and placental histopathology lack description. We report CNS and placental pathology in fetal cases with symptomatic COL4A1 mutation. METHODS: We retrieved four autopsy cases of COL4A1 related disease, confirmed by genetic sequencing after fetal brain injury was detected. RESULTS: One case was a midgestation fetus with residua of ventricular zone hemorrhage and normal placental villi. Three cases were 30-32 week gestation fetuses: two demonstrated CNS small vessel thrombosis, with CNS injury. Both demonstrated high grade placental fetal vascular malperfusion (FVM). One additionally showed villous dysmorphism, the other demonstrated mild villous immaturity. The fetus whose placenta demonstrated high grade FVM was growth restricted. A fourth fetus demonstrated schizencephaly with a CNS arteriopathy with smooth muscle cell degeneration and cerebral infarcts; the placenta demonstrated severe villous dysmorphism and low grade FVM. DISCUSSION: These cases confirm that small vessel disease is important in producing intracranial pathology in COL4A1mutation. We report an arteriopathy distinct from microvascular thrombosis and demonstrate that placental pathology is common in fetal COL4A1 related disease. This tentatively suggests that placental pathology may contribute to CNS abnormalities by affecting circulatory sufficiency.
Subject(s)
Brain/abnormalities , Collagen Type IV/genetics , Fetus/abnormalities , Placenta Diseases/genetics , Placenta/pathology , Female , Humans , Mutation , Placenta Diseases/pathology , PregnancyABSTRACT
Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease-causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.
Subject(s)
Abnormalities, Multiple/genetics , Brain Diseases/genetics , Fetal Growth Retardation/genetics , Genetic Association Studies , Ichthyosis/genetics , Limb Deformities, Congenital/genetics , Microcephaly/genetics , Phosphoglycerate Dehydrogenase/genetics , Transaminases/genetics , Female , Fetus , Humans , Infant, Newborn , Male , Mutation , Serine/biosynthesisABSTRACT
CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10-12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.
Subject(s)
CpG Islands , DNA Methylation , Myotonic Dystrophy/genetics , Myotonin-Protein Kinase/genetics , Adolescent , Adult , Base Sequence , Cell Line , Child , Female , Human Embryonic Stem Cells/chemistry , Humans , Linear Models , Male , Pedigree , Pregnancy , Promoter Regions, Genetic , Sequence Analysis, DNA , Young AdultABSTRACT
Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.
Subject(s)
Anencephaly/genetics , Cleft Lip/genetics , Cleft Palate/genetics , Microfilament Proteins/genetics , Anencephaly/complications , Anencephaly/pathology , Cleft Lip/complications , Cleft Lip/pathology , Cleft Palate/complications , Cleft Palate/pathology , Female , Fetus , Homozygote , Humans , Loss of Function Mutation/genetics , Microarray Analysis , Neural Tube Defects/genetics , Neural Tube Defects/pathologyABSTRACT
Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Glutamate-Ammonia Ligase/deficiency , Glutamate-Ammonia Ligase/genetics , Adult , Amino Acid Metabolism, Inborn Errors/pathology , Female , Fetus , Glutamine/genetics , Homozygote , Humans , Infant, Newborn , Male , Metabolic Diseases/genetics , Metabolic Diseases/pathologyABSTRACT
Our improved tools to identify the aetiologies in patients with multiple abnormalities resulted in the finding that some patients have more than a single genetic condition and that some of the diagnoses made in the past are acquired rather than inherited. However, limited knowledge has been accumulated regarding the phenotypic outcome of the interaction between different genetic conditions identified in the same patients. We report a newborn girl with brachytelephalangic chondrodysplasia punctata (BCDP) as well as frontonasal dysplasia, ptosis, bilateral hearing loss, vertebral anomalies, and pulmonary hypoplasia who was found, by whole exome sequencing, to have a de novo pathogenic variant in RAF1 (c.770C>T, [p.Ser257Leu]) and a likely pathogenic variant in SIX2 (c.760G>A [p.A254T]), as well as maternal systemic lupus erythematosus (SLE). This case shows that BCDP is most probably not a diagnostic entity and can be associated with various conditions associated with CDP including maternal SLE.
Subject(s)
Abnormalities, Multiple/genetics , Chondrodysplasia Punctata/genetics , Homeodomain Proteins/genetics , Nerve Tissue Proteins/genetics , Proto-Oncogene Proteins c-raf/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Chondrodysplasia Punctata/diagnosis , Chondrodysplasia Punctata/pathology , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Face/abnormalities , Face/pathology , Female , Genetic Predisposition to Disease , Hernia, Diaphragmatic/diagnosis , Hernia, Diaphragmatic/genetics , Humans , Infant, NewbornABSTRACT
OBJECTIVE: Near term unexpected stillbirth is a common, complex diagnostic challenge. We review a large cohort of near term to term gestation unexpected fetal deaths to document the common patterns of pathology and evaluate the utility of various standard autopsy procedures. METHODS: A total of 123 perinatal autopsies consisting of 94 intrauterine fetal deaths (IUFDs) and 29 intrapartum deaths (IPDs) were reviewed. Deaths were classified according to the laboratory investigations establishing cause of death. RESULTS: Cause of death was attributable to placental pathology without autopsy in 55.3% of IUFD and 17% of IPD. Correlative findings at autopsy increased the ability to establish cause of death in 86.2% of IUFD and 62% of IPD. Histology was largely corroborative, with the brain, lungs, and heart demonstrating significant changes in 46%, 34.5%, and 13.8%, respectively. Microbiology was corroborative but demonstrated single organism growth in 6 of 29 cases of fatal acute chorioamnionitis. Newborn metabolic screening revealed only elevated thyroid-stimulating hormone levels in 3 cases, of questionable relevance. Aneuploidy was established by screening molecular studies in 5 IUFDs, all of which had external or visceral dysmorphism. Karyotype was established in 69 cases and was not contributory in any of the IPD: 3 IUFDs had changes of unknown significance. Cause of death was not established at autopsy in 9% of IUFD and 10% of IPD. DISCUSSION: This is the largest uniformly investigated cohort of late gestation unexpected fetal deaths studied. We confirm the importance of both placental and fetal autopsy in establishing cause of death. Autopsy histology, microbiology, and cytogenetics provide important but largely corroborative data.