Intracranial calcifications simulating Aicardi-Goutières syndrome in PARS2-related mitochondrial disease.

PARS2 encodes an aminoacyl-tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl-tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile-onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals. About 10 individuals to date have been described with pathogenic biallelic variants in PARS2. While many of the reported individuals succumbed to the disease in the first two decades of life, autopsy findings have not yet been reported. Here, we describe neuropathological findings in a deceased male with evidence of intracranial calcifications in the basal ganglia, thalamus, cerebellum, and white matter, similar to Aicardi-Goutières syndrome. This report describes detailed autopsy findings in a child with PARS2-related mitochondrial disease and provides plausible evidence that intracranial calcifications may be a previously unrecognized feature of this disorder.

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.

Prenatal diagnosis and postnatal outcome of closed spinal dysraphism.

OBJECTIVE: To evaluate the prenatal diagnosis of closed dysraphism (CD) and its correlation with postnatal findings and neonatal adverse outcomes. METHODS: A retrospective cohort study including pregnancies diagsnosed with fetal CD by prenatal ultrasound (US) and magnetic resonance imaging (MRI) at a single tertiary center between September 2011 and July 2021. RESULTS: CD was diagnosed prenatally and confirmed postnatally in 12 fetuses. The mean gestational age of prenatal imaging was 24.2 weeks, in 17% the head circumference was ≤fifth percentile and in 25% the cerebellar diameter was ≤fifth percentile. US findings included banana sign in 17%, and lemon sign in 33%. On MRI, posterior fossa anomalies were seen in 33% of cases, with hindbrain herniation below the foramen magnum in two cases. Mean clivus-supraocciput angle (CSA) was 74°. Additional anomalies outside the CNS were observed in 50%. Abnormal foot position was demonstrated prenatally in 17%. Neurogenic bladder was present in 90% of patients after birth. CONCLUSION: Arnold Chiari II malformation and impaired motor function can be present on prenatal imaging of fetuses with CD and may be associated with a specific type of CD. Prenatal distinction of CD can be challenging. Associated extra CNS anomalies are frequent and the rate of neurogenic urinary tract dysfunction is high.

JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study.

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

TSEN54 Gene-Related Pontocerebellar-Hypoplasia and Role of Prenatal MR Imaging: Besides the Common Posterior Fossa Cystic Malformations.

Pontocerebellar-hypoplasia (PCH) related to TSEN54-gene mutation, a rare autosomal recessive disorder, can be associated with three different phenotypes: PCH2A, PCH4 and PCH5. Prenatal imaging features are very scant, in particular for PCH4 and PCH5. The aim of this letter is to illustrate key role of prenatal MR imaging in better evaluation of the cerebellar vermis-hemispheres and pons, which may lead to the differential diagnosis between three PCH TSEN54-related phenotypes already at mid-gestation based on the pattern of the degree of involvement of the vermis and the cerebellar cortex respectively.

Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in LSM11 and RNU7-1, components of the U7 small nuclear ribonucleoprotein (snRNP) complex, have been identified in a limited number of genetically unexplained AGS cases. Impairment of U7 snRNP function results in misprocessing of replication-dependent histone (RDH) pre-mRNA and disturbance of histone occupancy of nuclear DNA, ultimately driving cGAS-dependent type I interferon (IFN-I) release. OBJECTIVE: We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS. METHODS: Whole exome sequencing (WES) and targeted Sanger sequencing of RNU7-1 were performed. Primary fibroblasts were used for mechanistic studies. IFN-I signature and STAT1/2 phosphorylation were assessed in peripheral blood. Cytokines were profiled on serum and cerebrospinal fluid (CSF). Histopathology was examined on brain and kidney tissue. RESULTS: Sequencing revealed compound heterozygous RNU7-1 mutations, resulting in impaired RDH pre-mRNA processing. The 3' stem-loop mutations reduced stability of the secondary U7 snRNA structure. A discrete IFN-I signature in peripheral blood was paralleled by MCP-1 (CCL2) and CXCL10 upregulation in CSF. Histopathological analysis of the kidney showed thrombotic microangiopathy. We observed dysregulated STAT phosphorylation upon cytokine stimulation. Clinical overview of all reported patients with RNU7-1-related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes. CONCLUSIONS: Targeted RNU7-1 sequencing is recommended in genetically unexplained AGS cases. CSF cytokine profiling represents an additional diagnostic tool to identify aberrant IFN-I signaling. Clinical follow-up of RNU7-1-mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy.

Prenatal exome sequencing: A useful tool for the fetal neurologist.

Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.

Evaluation of prenatal central nervous system anomalies: obstetric management, fetal outcomes and chromosome abnormalities.

OBJECTIVE: To study the outcomes of fetuses who were diagnosed with central nervous system (CNS) anomalies during prenatal period and to describe the obstetric management of those pregnancies. METHODS: In this retrospective study, fetuses who were detected to have central nervous system anomalies by prenatal ultrasound from January 2010 to December 2019 were recruited. Data regarding prenatal diagnosis and obstetric outcomes were retrieved from maternal and paediatric records. The prognosis of fetuses who were born alive was classified based on their neurodevelopmental outcome within two years of life. RESULTS: There were a total of 365 fetuses with CNS anomalies within the 10-year study period, with a mean gestational age of 24.65±7.37 weeks at diagnosis. Ventriculomegaly (23.36%) was the commonest CNS anomalies seen. 198 (54.20%) of these fetuses had associated extra-CNS anomalies, with cardiovascular being the most common system involved. Fetal karyotyping was performed in 111 pregnancies, with chromosomal aberrations detected in 53 (49.07%) cases and culture failure in 3 cases. Majority of the chromosomal abnormalities were Edward syndrome (trisomy 18) and Patau syndrome (trisomy 13). Fetuses with congenital CNS anomalies and abnormal chromosomal karyotyping were more likely to be diagnosed earlier by prenatal ultrasound and tend to have poorer obstetric and neurocognitive prognosis. Prenatally, 86 (23.56%) of the cases were lost to follow up and likely to deliver elsewhere. Among the 279 cases whom their pregnancy outcomes were available, 139 (49.82%) pregnancies resulted in live births, 105 (37.63%) pregnancies were electively terminated, while the remaining 35 (12.54%) pregnancies ended in spontaneous loss. The decision of termination of pregnancy largely depends on mean diagnostic gestational age, presence of chromosomal aberrations and abnormal amniotic fluid volume in those fetuses. Two years after delivery, only 75 (53.96%) children out of 139 live births were still alive, 43 (30.93%) died and 21 (15.11%) cases were lost to follow-up. 32 (23.02%) children with prenatally diagnosed CNS anomalies had normal neurodevelopmental outcome. The presence of multiple CNS anomalies and involvement of extra-CNS anomalies indicated a poorer neurodevelopmental prognosis. CONCLUSION: Less than 50% of fetuses with prenatally diagnosed CNS anomalies resulted in live births. Even if they survive till delivery, 36.45% of them passed away within 2 years and 62.79% of children who survived till 2 years old had neurodevelopmental disability.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

White matter alteration and cerebellar atrophy are hallmarks of brain MRI in alpha-mannosidosis.

OBJECTIVE: Despite profound neurological symptomatology there are only few MRI studies focused on the brain abnormalities in alpha-mannosidosis (AM). Our aim was to characterize brain MRI findings in a large cohort of AM patients along with clinical manifestations. METHODS: Twenty-two brain MRIs acquired in 13 untreated AM patients (8 M/5F; median age 17 years) were independently assessed by three experienced readers and compared to 16 controls. RESULTS: Focal and/or diffuse hyperintense signals in the cerebral white matter were present in most (85%) patients. Cerebellar atrophy was common (62%), present from the age of 5 years. Progression was observed in two out of 6 patients with follow-up scans. Cortical atrophy (62%) and corpus callosum thinning (23%) were already present in a 13-month-old child. The presence of low T2 signal intensity in basal ganglia and thalami was excluded by the normalized signal intensity profiling. The enlargement of perivascular spaces in white matter (38%), widening of perioptic CSF spaces (62%), and enlargement of cisterna magna (85%) were also observed. Diploic space thickening (100%), mucosal thickening (69%) and sinus hypoplasia (54%) were the most frequent non-CNS abnormalities. CONCLUSION: White matter changes and cerebellar atrophy are proposed to be the characteristic brain MRI features of AM. The previously reported decreased T2 signal intensity in basal ganglia and thalami was not detected in this quantitative study. Rather, this relative MR appearance seems to be related to the diffuse high T2 signal in the adjacent white matter and not the gray matter iron deposition that has been hypothesized.

Identification of two novel de novo TUBB variants in cases with brain malformations: case reports and literature review.

Heterozygous variants in TUBB encoding one of ß-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.

A boy with biallelic frameshift variants in TTC5 and brain malformation resembling tubulinopathies.

Brain malformations have heterogeneous genetic backgrounds. Tubulinopathies are a wide range of brain malformations caused by variants in tubulin and microtubules-associated genes. Recently biallelic variants in TTC5, also known as stress responsive activator of p300, have been reported in 11 patients from seven families with developmental delay, intellectual disability, and brain malformations. Here, we report compound heterozygous frameshift variants in TTC5 in a Japanese boy who showed severe psychomotor developmental delay and pseudobulbar palsy with growth failure. Brain magnetic resonance imaging showed a simplified gyral pattern and undetectable anterior limb of the internal capsule, suggesting tubulinopathies. Immunoblotting using lymphoblastoid cells derived from the patient showed undetectable TTC5 protein. Ttc5 silencing by RNA interference in Neuro2a cells reduced Tubulin ß3 protein level and caused abnormal cell cycle. Our report suggests a possible link between TTC5-related brain malformation and tubulinopathies.

Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies.

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.

Phenotypic spectrum of the RBM10-mediated intellectual disability and congenital malformation syndrome beyond classic TARP syndrome features.

Pathogenic variants in the RBM10 gene cause a rare X-linked disorder described as TARP (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left vena cava superior) syndrome. We report two novel patients with truncating RBM10 variants in view of the literature, presenting a total of 26 patients from 15 unrelated families. Our results illustrate the highly pleiotropic nature of RBM10 pathogenic variants, beyond the classic TARP syndrome features. Major clinical characteristics include severe developmental delay, failure to thrive, brain malformations, neurological symptoms, respiratory issues, and facial dysmorphism. Minor features are growth retardation, cardiac, gastrointestinal, limb, and skeletal abnormalities. Additional recurrent features include genital and renal abnormalities as well as hearing and visual impairment. Thus, RBM10 loss of function variants typically cause an intellectual disability and congenital malformation syndrome that requires assessment of multiple organ systems at diagnosis and for which provided clinical features might simplify diagnostic assessment. Furthermore, evidence for an RBM10-related genotype-phenotype correlation is emerging, which can be important for prognosis.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Genetic disorders with central nervous system white matter abnormalities: An update.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

SCYL1 disease and liver transplantation diagnosed by reanalysis of exome sequencing and deletion/duplication analysis of SCYL1.

SCYL1 disease results from biallelic pathogenic variants in SCYL1. We report two new patients with severe hepatic phenotype requiring liver transplantation. Patient charts reviewed. DNA samples and skin fibroblasts were utilized. Literature was reviewed. 13-year-old boy and 9-year-old girl siblings had acute liver insufficiency and underwent living related donor liver transplantation in infancy with no genetic diagnosis. Both had tremor, global developmental delay, and cognitive dysfunction during their follow-up in the medical genetic clinic for diagnostic investigations after their liver transplantation. Exome sequencing identified a likely pathogenic variant (c.399delC; p.Asn133Lysfs*136) in SCYL1. Deletion/duplication analysis of SCYL1 identified deletions of exons 7-8 in Patient 1. Both variants were confirmed in Patient 2 and the diagnosis of SCYL1 disease was confirmed in both patients at the age of 13 and 9 years, respectively. SCYL1 protein was not expressed in both patients' fibroblast using western blot analysis. Sixteen patients with SCYL1 disease reported in the literature. Liver phenotype (n = 16), neurological phenotype (n = 13) and skeletal phenotype (n = 11) were present. Both siblings required liver transplantation in infancy and had variable phenotypes. Exome sequencing may miss the diagnosis and phenotyping of patients can help to diagnose patients.

AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination.

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants.

Individuals carrying biallelic loss-of-function mutations in PCDH12 have been reported with three different conditions: the diencephalic-mesencephalic junction dysplasia syndrome 1 (DMJDS1), a disorder characterized by global developmental delay, microcephaly, dystonia, and a midbrain malformation at the diencephalic-mesencephalic junction; cerebral palsy combined with a neurodevelopmental disorder; and cerebellar ataxia with retinopathy. We report an additional patient carrying a homozygous PCDH12 frameshift, whose anamnesis combines the most recurrent DMJDS1 clinical features, that is, global developmental delay, microcephaly, and ataxia, with exudative vitreoretinopathy. This case and previously published DMJDS1 patients presenting with nonspecific visual impairments and ophthalmic disorders suggest that ophthalmic alterations are an integral part of clinical features associated with PCDH12 loss-of-function.

Investigation of copeptin levels in foetal congenital central nervous system anomalies.

Copeptin has been shown to be associated with central nervous system pathologies. The aim of this study was to investigate the relationship between serum CCP levels and central nervous system (CNS) anomalies. In this case-control study, those at 9-14 weeks of gestation serum levels of copeptin, were assessed in pregnant women whose foetuses subsequently developed CNS anomalies (group 1: n = 60) and compared with gestational age-matched pregnant women who exhibited normal pregnancy outcomes (group 2: n = 48). The mean copeptin levels were 1.58 ± 0.40 ng/mL and 1.11 ± 0.36 ng/mL in the CNS anomalies and control groups, respectively (p < .0001). An increased level of copeptin independently predicts development of CNS anomalies, suggesting that copeptin can be used for prediction and discrimination of CNS anomalies in normal pregnancies at 9-14 weeks of gestation.Impact statementWhat is already known on this subject? There is no test or method to diagnose CNS anomalies in the first trimester of pregnancy. This study presents the first and new information on the relationship between serum copeptin levels and central nervous system anomalies in pregnant women whose foetuses subsequently developed CNS anomalies.What do the results of this study add? I have strongly demonstrated differences in maternal CPP levels between CNS anomalous pregnancies and healthy controls.What are the implications of these findings for clinical practice and/or further research? It has been thought that copeptin appears to be an ideal marker for central nervous system anomaly prediction at 9-14 weeks of gestational age and if confirmed in larger prospective studies. Finally, these results could not be used as parameters for prenatal CNS screening. Advanced studies, well-structured and conducted on larger populations are needed to investigate the issue further.