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Background: Brain anomalies (BAs) have been the focus of research, as they have a high impact on fetal health but therapeutic and diagnostic approaches are limited. Objectives: In this study, the application and efficiency of exome sequencing (ES) in detecting different cases of BAs in fetuses were evaluated and compared with chromosomal microarray analysis (CMA). Search strategy: To conduct this study, three databases including PubMed, Web of Science and Embase were utilised with the keywords 'prenatal', 'diagnoses', 'brain anomalies' and 'exome sequencing'. Selection criteria: Studies were included based on the STARD checklist, for which the ES and CMA diagnostic yields were calculated. Data collection and analysis: Meta‐analysis was performed on the included studies using a random‐effects model and subgroup analysis to define the risk difference between them. Main results: We included 11 studies representing 779 fetuses that implemented ES along with imaging techniques. The pooled ES diagnostic yield in fetuses with BAs detected through magnetic resonance imaging (MRI) and ultrasonography was 26.53%, compared with 3.46% for CMA. The risk difference between ES and CMA for complex BAs was 0.36 [95% confidence interval (CI) 0.24–0.47], which was higher than for single BAs (0.22; 95% CI 0.18–0.25]. Conclusions: ES is a useful method with a significantly higher diagnostic yield than CMA for genetic assessment of fetuses with complex BAs detected by imaging techniques. Moreover, ES could be applied to suspected fetuses with related family histories to predict congenital diseases with high efficiency. [ABSTRACT FROM AUTHOR]

Objective: The aim of this systematic review and meta-analysis was to compare the additional value of fetal neurosonography (NS) and fetal magnetic resonance imaging (MRI) in fetuses at risk for brain anomalies. Materials and Methods: This systematic review article was conducted based on PRISMA guidelines. On January 30, 2021, a systematic search was conducted using Embase, Medline, Web of Science, Scopus, and the Cochrane Library, with no language restrictions. The purpose was to identify all articles comparing NS with fetal MRI, in cases of suspected brain abnormalities. The statistical analysis was performed using STATA-15 and Meta-Disk 1.4 software. Results: Eight articles were included in this review. The overall agreement rate between NS and MRI was 81%. Data from NS changed the management of 6% of patients, and MRI data added data to the results of NS, in 9% of cases. In cases where the fetal MRI was normal, the added value of the postnatal MRI was 4%. Conclusion: When brain abnormalities are suspected, based on NS, MRI can play a significant role in the diagnostic path by clarifying the findings and significantly increasing the detection of abnormalities, especially when abnormalities are suspected in the posterior, midline, or cortical areas of the brain. [ABSTRACT FROM AUTHOR]

RHOA‐related neuroectodermal syndrome is characterised by linear skin hypopigmentation along Blaschko's lines associated with alopecia, leukoencephalopathy, facial and limb hypoplasia, and ocular, dental, and acral anomalies. Herein, we report a patient with patterned cutaneous hypopigmentation with a similar phenotype due to a novel postzygotic RHOA variant (c.210G>T; p.Arg70Ser). This illustrates that the complexity of the orchestration of morphogenesis and organogenesis can be affected by different variants in the same gene. [ABSTRACT FROM AUTHOR]

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities). [ABSTRACT FROM AUTHOR]

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell‐cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype–phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A. [ABSTRACT FROM AUTHOR]

Background: Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. Methods: Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. Results: Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. Conclusions: This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to delineate the clinical phenotype of patients with 9p deletions, pinpoint the chromosomal breakpoints, and identify the critical region for trigonocephaly, which is a frequent finding in 9p terminal deletion. Methods: We investigated a cohort of nine patients with chromosome 9p terminal deletions who all displayed developmental delay, intellectual disability, hypotonia, and dysmorphic features. Of them, eight had trigonocephaly, seven had brain anomalies, seven had autistic manifestations, seven had fair hair, and six had a congenital heart defect (CHD). Results: Karyotyping revealed 9p terminal deletion in all patients, and patients 8 and 9 had additional duplication of other chromosomal segments. We used six bacterial artificial chromosome (BAC) clones that could identify the breakpoints at 17–20 Mb from the 9p terminus. Array CGH identified the precise extent of the deletion in six patients; the deleted regions ranged from 16 to 18.8 Mb in four patients, patient 8 had an 11.58 Mb deletion and patient 9 had a 2.3 Mb deletion. Conclusion: The gene deletion in the 9p24 region was insufficient to cause ambiguous genitalia because six of the nine patients had normal genitalia. We suggest that the critical region for trigonocephaly lies between 11,575 and 11,587 Mb from the chromosome 9p terminus. To the best of our knowledge, this is the minimal critical region reported for trigonocephaly in 9p deletion syndrome, and it warrants further delineation. [ABSTRACT FROM AUTHOR]

Prenatal ultrasound (US) is the first prenatal imaging tool for screening and evaluation of posterior fossa malformations since it is noninvasive, widely available, and safe for both mother and child. Fetal MRI is a widely used secondary technique to confirm, correct, or complement questionable US findings and plays an essential role in evaluating fetuses with suspected US findings and /or positive family history. The main sequences of fetal MRI consist of T2‐weighted (T2w) ultrafast, single‐shot sequences. Axial, coronal, and sagittal images are typically acquired allowing for a detailed evaluation of the posterior fossa contents. Also, various complimentary sequences, such as T1w, T2*w gradient sequences, or advanced techniques, including diffusion‐weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy, may provide additional information based on the studied malformation. Inclusion of these techniques should be done with careful risk–benefit analysis. The use of fetal MRI also aims to evaluate for associated anomalies. In addition, prenatal diagnosis of posterior fossa malformations is still a challenge but advances in knowledge in human developmental anatomy, genetic, and imaging recognition patterns have enabled us to shed some light on prognostic information that will help with the counseling of families. Finally, high‐resolution late third trimester fetal MRI offers a safe alternative to early postnatal MR imaging, basically taking advantage of the uterine environment as a kind of "maternal incubator." Our goal is to discuss the spectrum of prenatal posterior fossa pathologies that can be studied by fetal MRI and their key neuroimaging features. [ABSTRACT FROM AUTHOR]

Pfeiffer syndrome (PS) is a rare autosomal dominant craniofacial disorder characterized by primary craniosynostosis, midface hypoplasia, and extremities' abnormalities including syndactyly. The purpose of this article was to review the current knowledge regarding how PS affects the nervous system. Methodologically, we conducted a systematic review of the existing literature concerning involvement of the nervous system in PS. Multiple-suture synostosis is common, and it is the premature fusion and abnormal growth of the facial skeleton's bones that cause the characteristic facial features of these patients. Brain abnormalities in PS can be primary or secondary. Primary anomalies are specific developmental brain defects including disorders of the white matter. Secondary anomalies are the result of skull deformity and include intracranial hypertension, hydrocephalus, and Chiari type I malformation. Spinal anomalies in PS patients include fusion of vertebrae, "butterfly" vertebra, and sacrococcygeal extension. Different features have been observed in different types of this syndrome. Cloverleaf skull deformity characterizes PS type II. The main neurological abnormalities are mental retardation, learning difficulties, and seizures. The tricky neurological examination in severely affected patients makes difficult the early diagnosis of neurological and neurosurgical complications. Prenatal diagnosis of PS is possible either molecularly or by sonography, and the differential diagnosis includes other craniosynostosis syndromes. Knowing how PS affects the nervous system is important, not only for understanding its pathogenesis and determining its prognosis but also for the guidance of decision-making in the various critical steps of its management. The latter necessitates an experienced multidisciplinary team. [ABSTRACT FROM AUTHOR]

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created 'matching' platforms. We describe four individuals from three unrelated families 'matched' by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as 'pathogenic.' TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder. [ABSTRACT FROM AUTHOR]

ABSTRACT Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Anterior encephaloceles are rare conditions. Except for a few places from South East Asia, no large series has been published in the World literature. Materials and Methods: At AIIMS, we have managed 133 cases over a 40-year-period from 1971 to 2010. Frontoethmoidal type was the most frequent, noticed in 104 patients, followed by nasopharyngeal nasal in 12 and orbital encephaloceles in 6 patients. Observation: Ten patients were adults over the age of 18 years and 15 patients were between 5 and 18 years of age. Swelling over the nose was reported in all 104 patients with frontoethmoid type. In nasopharyngeal type, patients presented with respiratory problem. Patients with orbital mass had proptosis, on the side of encephalocele. Computed tomography (CT)/Magnetic resonance imaging (MRI) was performed in 127 patients, which was able to delineate the bone defect and associated brain anomalies. All the patients were subjected to repair of encephalocele. Patients with hypertelorism required orbital osteotomies and correction of deformity. Outcome: There were four deaths, all prior to 2000. No death was encountered in the last 10 years. CSF leak was the commonest postoperative complication, noticed in 24 patients. Overall cosmetic outcome was good. [ABSTRACT FROM AUTHOR]

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome. [ABSTRACT FROM AUTHOR]

Galloway–Mowat syndrome (GMS) is a rare autosomal recessive disorder characterized by early onset nephrotic syndrome and microcephaly with various anomalies of the central nervous system. GMS likely represents a heterogeneous group of disorders with hitherto unknown genetic etiology. The clinical phenotype to some extent overlaps that of Pierson syndrome (PS), which comprises congenital nephrotic syndrome and distinct ocular abnormalities but which may also include neurodevelopmental deficits and microcephaly. PS is caused by mutations of LAMB2, the gene encoding laminin β2. We hypothesized that GMS might be allelic to PS or be caused by defects in proteins that interact with laminin β2. In a cohort of 18 patients with GMS or a GMS-like phenotype we therefore analyzed the genes encoding laminin β2 ( LAMB2), laminin α5 ( LAMA5), α3-integrin ( ITGA3), β1-integrin ( ITGB1) and α-actinin-4 ( ACTN4), but we failed to find causative mutations in these genes. We inferred that LAMA5, ITGA3, ITGB1, and ACTN4 are not directly involved in the pathogenesis of GMS. We excluded LAMB2 as a candidate gene for GMS. Further studies are required, including linkage analysis in families with GMS to identify genes underlying this disease. [ABSTRACT FROM AUTHOR]

Unilateral megalencephaly is a rare anomaly of the brain which causes enlargement of a lobe or an nentire hemisphere. The radiological features of the disease are a poorly defined unusual mass effect on PEG, angiography and CT scan. Pathologically, the disease is thought to be due to abnormal cell migration in the 3rd month in utero. [ABSTRACT FROM AUTHOR]

Encephalocraniocutaneous lipomatosis (ECCL) is a rare sporadic neurocutaneous syndrome characterized by presence of central nervous system, ocular and cutaneous anomalies. The exact pathogenesis is still not known. We present the third case from the Indian subcontinent, who is a five year old girl with history of right sided seizures. Dermatological examination showed alopecia on right side of the scalp and ipsilateral limbal dermoid and nodular skin tags over the upper eyelid. The computerized tomography scan of the brain revealed porencephalic cyst, cerebral calcifications and atrophy of right brain. The histopathology of the skin lesions showed lipomatous hamartoma and features of non scarring alopecia. The constellation of these findings and in adherence to the diagnostic criteria of ECCL proposed in 2009, we consider this report as a definite case of ECCL. [ABSTRACT FROM AUTHOR]

We describe a single case of a polymalformational syndrome in which the MR findings were of great help in the final diagnosis of Smith-Lemli-Opitz syndrome (SLOS) type I. MRI was performed for evaluation of the brain morphology since the clinical and laboratory findings were suggestive but not unequivocally indicative of SLOS. MRI findings of frontal lobe hypoplasia, cortical migration defect, and abnormalities of median line structures prompted the final diagnosis of SLOS. [ABSTRACT FROM AUTHOR]

Background: WNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established. Case presentation: Here we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5′ truncating mutation to date. Conclusion: This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development. [ABSTRACT FROM AUTHOR]