Genomic abnormalities in apparently isolated polyhydramnios and the role of confirmed fetal phenotype: a systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the rate of genomic abnormalities detected in pregnancies with apparently isolated hydramnios and explore the role of confirmed fetal phenotype. DATA SOURCES: PubMed, Cochrane Library, Google Scholar and Scopus databases were searched up to May 4, 2024. STUDY ELIGIBILITY CRITERIA: Observational studies, published after the year 2000 and written in a European language, reporting on the genomic outcome of pregnancies complicated with prenatally diagnosed isolated polyhydramnios were included in this meta-analysis. STUDY APPRAISAL AND SYNTHESIS METHODS: The main outcome was the incidence of genomic abnormalities, defined as chromosomal numerical or structural anomalies or monogenic syndromes, diagnosed prenatally or postnatally in neonates from pregnancies complicated with isolated polyhydramnios. Additional outcomes included the incidence of chromosomal abnormalities including both numerical and structural aberrations of the chromosomes (detected by karyotype/chromosomal microarray [CMA]), monogenic abnormalities (detected by next-generation sequencing [NGS] or clinical genetic examination after the result of a normal karyotype/CMA), genetic syndromes in general (diagnosed clinically with or without genetic confirmation), and structural abnormalities detected postnatally. Pooled proportions were calculated for each outcome. RESULTS: Twelve studies (2561 pregnancies complicated with isolated hydramnios) were included in the meta-analysis. The pooled prevalence of genomic anomalies in fetuses with apparently isolated polyhydramnios (12 studies, 2634 fetuses) was 4.5% (95%CI 2.6-7.6). The pooled prevalence of chromosomal abnormalities (11 studies, 2427 fetuses) was 2.1% (95%CI 1.1-3.7). The proportion of major structural defects detected postnatally (9 studies, 1731 fetuses) was 2.9% (95%CI 1.5-5.4); in this particular subgroup (4 studies, 14 fetuses), the pooled prevalence of genomic anomalies was 29.8% (95%CI 11.3-58.6). A meta-regression analysis indicated that the rate of genomic anomalies was positively associated with the severity of hydramnios. Also, the pooled rate of monogenic anomalies was 5.6% (95%CI 2-5; I2 =58%) in the two studies using NGS for genomic diagnosis. CONCLUSIONS: This meta-analysis showed that the rate of genomic anomalies in apparently isolated polyhydramnios is 4.5%; approximately half of them are chromosomal abnormalities and the other half are non-chromosomal genomic anomalies. From a clinical standpoint, CMA and possibly NGS could be considered even in cases of apparently isolated polyhydramnios; this may be even more important in cases of incomplete fetal phenotype. Further studies using NGS and addressing cost-effectiveness issues would fine-tune such recommendations.

A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1.

Cantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain-of-function (GOF) variants in KCNJ8 or ABCC9 that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside-out patch-clamp assays of KATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP-binding cassette (ABC) protein ion channels.

The Effect of Maternal Diet and Physical Activity on the Epigenome of the Offspring.

The aim of this review was to examine the current literature regarding the effect of maternal lifestyle interventions (i.e., diet and physical activity) on the epigenome of the offspring. PubMed, Scopus and Cochrane-CENTRAL were screened until 8 July 2023. Only randomized controlled trials (RCTs) where a lifestyle intervention was compared to no intervention (standard care) were included. Outcome variables included DNA methylation, miRNA expression, and histone modifications. A qualitative approach was used for the consideration of the studies' results. Seven studies and 1765 mother-child pairs were assessed. The most common types of intervention were dietary advice, physical activity, and following a specific diet (olive oil). The included studies correlated the lifestyle and physical activity intervention in pregnancy to genome-wide or gene-specific differential methylation and miRNA expression in the cord blood or the placenta. An intervention of diet and physical activity in pregnancy was found to be associated with slight changes in the epigenome (DNA methylation and miRNA expression) in fetal tissues. The regions involved were related to adiposity, metabolic processes, type 2 diabetes, birth weight, or growth. However, not all studies showed significant differences in DNA methylation. Further studies with similar parameters are needed to have robust and comparable results and determine the biological role of such modifications.

X-linked hypophosphatemia due to a de novo novel splice-site variant in a 7-year-old girl with scaphocephaly, Chiari syndrome type I and syringomyelia.

X-linked hypophosphatemia (XLH) is a rare X-linked dominant inherited disorder caused by loss-of-function variants in the PHEX gene and characterized by renal phosphate wasting, hypophosphatemia, abnormal vitamin D metabolism, growth retardation and lower limb deformities. We describe a case of XLH-rickets in a 7-year-old girl with scaphocephaly, Chiari syndrome type I and syringomyelia, with a de novo non-canonical splice variant (c.1080-3C > G) in intron 9 of the PHEX gene, that has not been previously described.

Beckwith-Wiedemann syndrome with multiple hepatic and cutaneous hemangiomas in a female patient of Albanian origin: Diagnostic and therapeutic considerations.

We describe a 2-month-old female infant with macroglossia, macrosomia, omphalocele, neonatal hypoglycemia, earlobe creases, low nasal bridge, midface retrusion, syndromic facies and multiple cutaneous and hepatic hemangiomas (HH). Genetic evaluation confirmed the diagnosis of Beckwith-Wiedemann Syndrome (BWS) with mosaic uniparental disomy 11 as the underlying genetic mechanism suggested by partial hypermethylation of H19/IGF2:IG-DMR and partial hypomethylation of KCNQ1OT1:TSS-DMR on chromosome 11p15.5. Pediatric endocrinology and cardiology assessments were normal. No malignant liver or renal tumors were detected during the follow-up period. Treatment with propranolol was started for the multiple HH, according to international recommendations. At 3-, 6-, and 9-month follow up, a gradual decrease in the size of the hemangiomas and AFP levels was observed, without side effects. This is the fifth case in the literature combining HH and BWS, and among these, the third case with this specific genetic defect suggesting a possible association between HH and BWS caused by 11 paternal uniparental disomy [upd(11)pat]. The case also highlights that if treatment is warranted, then oral propranolol can be used for the management of infantile HH in BWS patients similarly to non-BWS patients.

Female carrier of RPGR mutation presenting with high myopia.

BACKGROUND: Inherited retinopathies can initially present with high refractive error in the first decade of life, before accompanying signs or symptoms are evident. CASE PRESENTATION: A 4-year-old girl with high myopia (S-12.00 C-4.00 × 20 in the right and S-14.50 C-2.75 × 160 in the left eye), moderate visual acuity (0.3 logMAR in the right and 0.4 logMAR in the left eye), and left esotropia, presented with unremarkable past medical history and no family history of high refractive error or low vision. In optical coherence tomography imaging, macular thinning was evident, while morphology was normal. Full-field electroretinogram revealed normal implicit time recordings with reduced amplitudes in scotopic and photopic conditions. Fundus autofluorescence showed a radial pattern in both eyes. During a 5-year follow-up, significant myopia progression ensued (S-17.25 C-3.00 × 20 in the right and S-17.25 C-2.00 × 160 in the left eye), with a corresponding increase in axial length and an unchanged visual acuity. Whole-exome sequencing revealed a heterozygous termination codon variant c.212C>G (p.Ser71Ter) in RPGR, considered to be pathogenic. Segregation analysis precluded the variation in the mother and sister. A random pattern of X-chromosome inactivation was detected in the proband, without X-chromosome inactivation deviation. CONCLUSION: This is the second report associating this specific RPGR mutation with high myopia and the first report to identify it in a female proband. This case provides additional evidence on the genotypic-phenotypic correlation between RPGR c.212C>G mutation and high myopia.

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

Bowel Perforation in Vascular Ehlers-Danlos Syndrome: Case Report and Comprehensive Review.

INTRODUCTION: Ehlers-Danlos syndromes (EDS) comprise a rare variety of genetic disorders, affecting all types of collagen. Herein, we describe a case of the vascular type of EDS, with coexisting segmental absence of intestinal musculature, while simultaneously performing a narrative review of the existing literature. CASE PRESENTATION: A 23-year-old male patient with a history of multiple abdominal operations due to recurrent bowel perforations and the presence of a high-output enterocutaneous fistula was admitted to our surgical department for further evaluation and treatment. After detailed diagnostic testing, the diagnosis of vascular-type EDS (vEDS) was made and a conservative therapeutic approach was adopted. In addition, a comprehensive review of the international literature was carried out by applying the appropriate search terms. RESULTS: The diagnosis of vEDS was molecularly confirmed by means of genetic testing. The patient was treated conservatively, with parenteral nutrition and supportive methods. Thirty-four cases of bowel perforation in vEDS have been reported so far. Interestingly, this case is the second one ever to report co-existence of vEDS with Segmental Absence of Intestinal Musculature. CONCLUSIONS: Establishing the diagnosis of vEDS promptly is of vital significance in order to ensure that patients receive appropriate treatment. Due to initial non-specific clinical presentation, EDS should always be included in the differential diagnoses of young patients with unexplained perforations of the gastrointestinal tract.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Treatment-resistant manic episode in a patient diagnosed with bipolar affective disorder.

A considerable group of patients suffering from mental health disorders do not respond adequately to pharmacological treatment. For the purposes of precision and personalized medicine, pharmacogenomics has been developed as a valuable and promising tool. The technology of identifying single nucleotide polymorphisms and genotyping supplies clinicians, and therefore their patients, with the opportunity of avoiding long-lasting 'trial and error' periods, reducing the risk of manifesting disturbing adverse effects during treatment. Consequently, better adherence to treatment and clinical response can be achieved, contributing to personalized treatment planning, according to a person's genetic profile and needs. In the present report, we present a case of an individual diagnosed with bipolar affective disorder type I, who showed resistance to pharmacological treatment and underwent through pharmacogenomic investigations, in order to identify the appropriate medication for the best possible clinical response.

Expanding the phenotype of TAB2 variants and literature review.

TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome sequencing. Eight individuals had de novo variants, the other six individuals were found to have maternally inherited, or likely maternally inherited, variants. Five individuals from the same family were identified following cardiac disease gene panel in the proband and subsequent targeted familial gene sequencing. The clinical features of this cohort were compared to the existing literature. Common clinical features include distinctive facial features, growth abnormalities, joint hypermobility, hypotonia, and developmental delay. Newly identified features included feeding difficulties, sleep problems, visual problems, genitourinary abnormality, and other anatomical variations. Here we report 14 new individuals, including novel TAB2 variants, in order to expand the emerging syndromic clinical phenotype and provide further genotype-phenotype correlation.

Lethal COG6-CDG in neonatal patient with arachnodactyly, joint contractures, and skin manifestations: Founder mutation in the Southeastern European population?

Herein, we report a lethal case of the ultra-rare COG6-congenital disorder of glycosylation (CDG) presenting with skin manifestations (scaling and erosions) and joint contractures in a neonate of Albanian origin. The patient was homozygous for a COG6 pathogenic variant, previously reported in another three individuals of Greek, Bulgarian and Turkish descent. The presence of a founder mutation in the geographical area is possible. The index case emphasizes the need to consider CDGs in neonatal patients with skin manifestations and joint contractures, particularly patients of Southeastern European or West Asian origin.

Novel Hemizygous Missense Variant of Spermine Synthase (SMS) Gene Causes Snyder-Robinson Syndrome in a Four-Year-Old Boy.

Snyder-Robinson syndrome (SRS) is an extremely rare X-linked intellectual disability syndrome (MRXSSR; MIM #309583). The main clinical features of SRS include psychomotor delay, hypotonia, and asthenic-type body habitus - reduced body weight and bone abnormalities (osteoporosis, fractures, kyphoscoliosis). We report a case of SRS with a hemizygous missense variant in the SMS gene,c.334C>G (p.Pro112Ala), in a 4-year-old boy, who initially developed hypotonia, delayed motor skills, and subsequently epilepsy. This variant in SMS was found to be de novo. To the best of our knowledge, this novel SMS gene variant has never been previously reported in disease-related variation databases, such as ClinVar or HGMD.

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.

KIF1A-related disorders in children: A wide spectrum of central and peripheral nervous system involvement.

KIF1A-related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood-onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case-notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent-but sometimes progressive-changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.

Angelman Syndrome due to a Maternally Inherited Intragenic Deletion Encompassing Exons 7 and 8 of the UBE3A Gene.

Angelman syndrome (AS) is characterised by developmental delay, lack of speech, seizures, a characteristic behavioural profile with a happy demeanour, microcephaly, and ataxia. More than two-thirds of cases are due to an approximately 5-Mb interstitial deletion of the imprinted region 15q11.2q13, which is usually de novo. The rest are associated with point mutations in the UBE3A gene, imprinting defects, and paternal uniparental disomy. Small intragenic UBE3A deletions have rarely been described. They are usually maternally inherited, increasing the recurrence risk to 50%, and may be missed by conventional testing (methylation studies and UBE3A gene sequencing). We describe a boy with AS due to an 11.7-kb intragenic deletion. The deletion was identified by array-CGH and was subsequently detected in his affected first cousin and unaffected maternal grandfather, mother, and aunt, confirming the silencing of the paternal allele. The patient had developmental delay, speech impairment, a happy demeanour, microcephaly, and an abnormal EEG, but no seizures by the age of 4 years. Delineation of the underlying genetic mechanism is of utmost importance for reasons of genetic counselling, as well as appropriate management and prognosis. Alternative techniques, such as array-CGH and MLPA, are necessary when conventional testing for AS has failed to identify the underlying genetic mechanism.