Specific T-cell subsets have a role in anti-viral immunity and pathogenesis but not viral dynamics or onwards vector transmission of an important livestock arbovirus.

Introduction: Bluetongue virus (BTV) is an arthropod-borne Orbivirus that is almost solely transmitted by Culicoides biting midges and causes a globally important haemorrhagic disease, bluetongue (BT), in susceptible ruminants. Infection with BTV is characterised by immunosuppression and substantial lymphopenia at peak viraemia in the host. Methods: In this study, the role of cell-mediated immunity and specific T-cell subsets in BTV pathogenesis, clinical outcome, viral dynamics, immune protection, and onwards transmission to a susceptible Culicoides vector is defined in unprecedented detail for the first time, using an in vivo arboviral infection model system that closely mirrors natural infection and transmission of BTV. Individual circulating CD4+, CD8+, or WC1+ γδ T-cell subsets in sheep were depleted through the administration of specific monoclonal antibodies. Results: The absence of cytotoxic CD8+ T cells was consistently associated with less severe clinical signs of BT, whilst the absence of CD4+ and WC1+ γδ T cells both resulted in an increased clinical severity. The absence of CD4+ T cells also impaired both a timely protective neutralising antibody response and the production of IgG antibodies targeting BTV non-structural protein, NS2, highlighting that the CD4+ T-cell subset is important for a timely protective immune response. T cells did not influence viral replication characteristics, including onset/dynamics of viraemia, shedding, or onwards transmission of BTV to Culicoides. We also highlight differences in T-cell dependency for the generation of immunoglobulin subclasses targeting BTV NS2 and the structural protein, VP7. Discussion: This study identifies a diverse repertoire of T-cell functions during BTV infection in sheep, particularly in inducing specific anti-viral immune responses and disease manifestation, and will support more effective vaccination strategies.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.

Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.

Lung Hypoplasia in Fetuses with Skeletal Dysplasia Determined by Fetal Lung Weight: Which Ultrasound Measurement/Ratio Has the Highest Detection Rate.

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.

Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

Medication Abortion Follow-Up Rates in a Rural Population Before and After Introduction of a Remote Follow-Up Option.

Background: Medication abortion (MAB) follow-up historically involves visiting a health care facility for ultrasonography or laboratory testing. In rural states such as New Mexico, many patients travel hours for MAB, making two visits burdensome. Studies demonstrate feasibility, safety, and patient preference for remote follow-up. Materials and Methods: We evaluated whether MAB follow-up by telephone had noninferior loss-to-follow-up (LTFU) rates compared with ultrasonography or laboratory follow-up in a rural population. This was a retrospective chart review of University of New Mexico MAB LTFU rates after changing to telephone follow-up (home group, n = 136). Patients were propensity-matched in a 1:2 ratio to a historical cohort (health care group, n = 272) to eliminate significant differences. We defined LTFU as no contact within 50 days. We evaluated complications requiring intervention, possible ongoing pregnancy, completion of the home follow-up protocol (7- and 30-day calls, high-sensitivity urine pregnancy test [UPT]), follow-up by intended method (home or health care), and number of call attempts. Results: LTFU rates for the home group (n = 23, 17%) were noninferior to the health care group (n = 60, 22%, p = 0.24). Rates of complications requiring intervention (p = 0.83) and possible ongoing pregnancy (p = 0.72) among the home group were similar to the health care group. Ninety-seven (71%) home group patients completed the initial call, 79 (58%) completed the UPT, and 86 (69%) completed the 30-day call. Ninety-five (70%) home group patients followed up by intended method, comparable with the health care group (n = 199, 73%, p = 0.56). Staff made a median of 3 (interquartile range: 2-4) calls per home group patient. Conclusions: Remote MAB LTFU rates were noninferior to in-person LTFU rates.

Anterior extension of the choroid plexus into the frontal horns of the fetal lateral cerebral ventricles: Prenatal findings and postnatal outcome.

OBJECTIVE: To evaluate the short- and long-term outcome of fetuses with evidence of extension of the choroid plexus into the frontal horns. METHODS: This is a retrospective cohort study of fetuses diagnosed with isolated choroid plexi extending into the frontal horns. Fetuses with major central nervous system anomalies were excluded. Ultrasound and fetal/postnatal magnetic resonance imaging (MRI) were evaluated. Postnatal outcomes, including developmental assessment, were obtained. RESULTS: Twenty nine fetuses were diagnosed with choroid plexus extension (22 unilateral and 7 bilateral). Gestational age at diagnosis was 19.3 weeks. Three cases (10.3%) presented with nonspecific extra-CNS findings. At presentation, 8/29 (28%) cases had single/multiple choroid plexus cysts (CPC). Twenty-six (89.6%) cases underwent antenatal MRI. On MRI, four cases had punctate susceptibility weighted imaging (SWI) foci suggesting trace hemosiderin and two cases had ventriculomegaly. Antenatal follow-up demonstrated resolution of the choroid plexus extension in 90% (18/20). Gestational age at delivery was 39.6 weeks. All had normal neurologic examinations within 24 h of life. Postnatal MRI studies were notable for deep venous differences in seven cases. Long-term clinical outcome was assessed in 14 cases with a median follow-up of 1.75 years, with normal neurodevelopment reported in 13/14 (92.8%). CONCLUSIONS: Most fetuses with an anterior extension of the choroid plexus as the sole sonographic finding had favorable outcomes.

Diagnosis of TBC1D32-associated conditions: Expanding the phenotypic spectrum of a complex ciliopathy.

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.

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series.

OBJECTIVE: Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging. METHODS: A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy. RESULTS: Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2). CONCLUSION: The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning.

Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort.

PURPOSE: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. METHODS: Clinical data was collected through an extensive web-based survey. RESULTS: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). CONCLUSION: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.

The Diverse Phenotype of Intestinal Dysmotility Secondary to ACTG2-related Disorders.

BACKGROUND AND AIMS: The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease. METHODS: Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored. RESULTS: One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P  = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores. CONCLUSIONS: Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.

Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies.

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.

Mapping the cellular origin and early evolution of leukemia in Down syndrome.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder.

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.

ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.

Brain and Placental Pathology in Fetal COL4A1 Related Disease.

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.

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.

PURPOSE: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Fetal Macrocephaly: A Novel Sonographic Finding in Congenital Myotonic Dystrophy.

Objective Sonographic clues to the diagnosis of congenital myotonic dystrophy (CDM) are limited, particularly in the absence of family history of myotonic dystrophy (DM). We reviewed cases of CDM for unique prenatal findings. Study Design A single-center case series of fetuses with CMD with characteristic prenatal findings confirmed postnatally. Results Four fetuses with pre- or postnatally diagnosed CDM presented with macrocephaly in utero. While head measurements were appropriate for gestational age until midgestation, third-trimester head circumference and biparietal diameter were both >2 standard deviation (SD) above the mean in all. Abdominal and femur measurements were otherwise appropriate for gestation. Postnatally, the occipitofrontal circumference was >2 SD above the mean in all, confirming the diagnosis of macrocephaly. Conclusion CDM should be included in the differential diagnosis of third-trimester macrocephaly, especially in the presence of additional sonographic clues and when maternal medical history and physical examination are suggestive of DM.