Wolf-Hirschhorn Syndrome Research Articles

Prenatal diagnosis for a fetus with 5p deletion syndrome

To explore the genetic basis for a fetus with club foot detected upon mid-pregnancy ultrasonography. Amniotic fluid of the fetus and peripheral blood samples of its parents were collected and subjected to G-banding karyotype analysis and copy number variation sequencing (CNV-seq). The result was verified by fluorescence in situ hybridization (FISH). The fetus and its parents all had a normal karyotype. CNV-seq analysis revealed that the fetus has harbored a 23.12 Mb on chromosome 5 and a 21.46 Mb duplication on chromosome 7. FISH assay has verified that its mother has carried a cryptic t(5;7)(p14.3;q33) translocation. CNV-seq combined with FISH can effectively detect cryptic chromosome aberrations, and can help to reduce severe birth defects and provide a basis for prenatal genetic counseling.

Síndrome de Cri Du Chat (síndrome do miado de gato) e a inclusão escolar

This study offers reflections on the inclusion of children with Cri Du Chat Syndrome (CCS), a rare condition of genetic origin. OBJECTIVES: To discuss the inclusion of children with CCS in schools and describe the characteristics, diagnosis, treatment, and main symptoms of the condition, along with the main difficulties students with CCS might face; to assess the knowledge teachers have about CCS and potential teaching resources they may use. METHOD: A digital survey questionnaire was used in this qualitative exploratory descriptive study. RESULTS: Only 14.8% of the 27 teachers who responded the questionnaire had knowledge about CCS and had worked in a classroom with adapted pedagogical practices. CONCLUSION: A very small portion of teachers had knowledge about CCS and most had never been in contact with individuals with the syndrome, either in a classroom or during training. A path has to be developed for the inclusion of children with CCS, through a process based on knowledge, affection, love, and respect for differences.

Anaesthetic Considerations for General Anaesthesia in an Adult Patient with Wolf-Hirschhorn Syndrome and Kyphoscoliosis: A Case Report

Wolf-Hirschhorn Syndrome (WHS), also known as Chromosome 4 deletion syndrome, is a rare hereditary disease with a prevalence of 1 in 50,000. It occurs due to the microdeletion of the short arm of chromosome 4, specifically the 4p16.3 domain. Patients with WHS exhibit diverse phenotypes, including growth retardation, developmental delay, congenital heart disease, and convulsions, depending on the amount of deleted genetic material. This case report focuses on a 25-year-old male who was admitted for cataract extraction and posterior chamber intraocular lens implantation. Through gene analysis, the patient was diagnosed with WHS. He exhibited micrognathia, a short neck, kyphoscoliosis, seizure disorder, and mental retardation. Additionally, he had severe kyphoscoliosis, which resulted in restrictive lung disease. These abnormalities posed significant challenges for anaesthetic management. To ensure a successful general anaesthesia, adequate preparedness for difficult airway management was crucial. A thorough cardiovascular and neuromuscular examination was conducted preoperatively to rule out associated anomalies and minimise complications. The patient’s perioperative antiepileptic cover was continued. Extubation proved challenging due to the patient’s mental retardation and restrictive lung disease. This case underscores the importance of effective anaesthetic management for patients with this rare condition undergoing cataract surgery under general anaesthesia.

Síndrome Cri Du Chat: relato de um caso neonatal e evolução até os nove meses de idade

Cri Du Chat Syndrome (SCDC) is a genetic syndrome that must be recognized and diagnosed as soon as possible for early follow-up and multidisciplinary intervention. We describe the case of a female newborn who was suspected at SCDC at delivery room due to high-pitched crying and facial asymmetry. We also describe the investigation until the final diagnosis and the clinical evolution up to nine months of age of the child. After the diagnosis was confirmed, our pacient received hospital discharge with follow-up of multidisciplinary team in order to reduce development impairments.

SÍNDROME CRI DU CHAT: RELATO DE UM CASO NEONATAL E EVOLUÇÃO ATÉ OS NOVE MESES DE IDADE

Cri Du Chat Syndrome (SCDC) is a genetic syndrome that must be recognized and diagnosed as soon as possible for early follow-up and multidisciplinary intervention. We describe the case of a female newborn who was suspected at SCDC at delivery room due to high-pitched crying and facial asymmetry. We also describe the investigation until the final diagnosis and the clinical evolution up to nine months of age of the child. After the diagnosis was confirmed, our pacient received hospital discharge with follow-up of multidisciplinary team in order to reduce development impairments.

Huntingtin Decreases Susceptibility to a Spontaneous Seizure Disorder in FVN/B Mice.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

Genetically unresolved case of Rauch-Steindl syndrome diagnosed by its wolf-hirschhorn associated DNA methylation episignature.

Wolf-Hirschhorn syndrome (WHS) is caused by deletion of a critical region of the short arm of chromosome 4. Clinical features of WHS include distinct dysmorphic facial features, growth restriction, developmental delay, intellectual disability, epilepsy, and other malformations. The NSD2 gene localizes within this critical region along with several other genes. Pathogenic variants in NSD2 cause Rauch-Steindl (RAUST) syndrome. Clinical features of RAUST syndrome partially overlap with WHS, however epilepsy and the recognizable facial gestalt are not observed. Here, we report a case of a young boy who presented with developmental delay, dysmorphic features and short stature. After negative chromosomal microarray and whole exome sequencing, genomic DNA methylation episignature analysis was performed. Episignatures are sensitive and specific genome-wide DNA methylation patterns associated with a growing number of rare disorders. The patient was positive for the WHS episignature. Reanalysis of the patient's exome data identified a previously undetected frameshift variant in NSD2, leading to a diagnosis of RAUST. This report demonstrates the clinical utility of DNA methylation episignature analysis for unresolved patients, and provides insight into the overlapping pathology between WHS and RAUST as demonstrated by the similarities in their genomic DNA methylation profiles.

Гетерогенность механизмов формирования хромосомного дисбаланса при синдроме Вольфа-Хиршхорна

Синдром Вольфа-Хиршхорна (WHS, OMIM 194190) - это один из наиболее частых микроделеционных синдромов, представленный гетерозиготной делецией короткого плеча хромосомы 4 (4p16.3). К основным клиническим проявлениям относят характерные черепно-лицевые дизморфии («шлем греческого воина»), пренатальный и постнатальный дефицит роста, задержку психо-речевого развития и судороги. На сегодняшний день описано несколько механизмов формирования делеций 4р16.3 и несколько критических областей, ответственных за фенотипические проявления у пациентов. В нашем исследовании мы представляем пять случаев делеции 4p16.3, имеющей различное происхождение и механизмы формирования. Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is one of the most common microdeletion syndromes, represented by a heterozygous deletion of the short arm of chromosome 4 (4p16.3). The main clinical features of patients with WHS include: craniofacial features - “Greek warrior helmet”, prenatal and postnatal growth deficiency, developmental disability of variable degree, and seizures. To date, several mechanisms for the formation of 4p16.3 deletions and several critical regions responsible for phenotypic manifestations in patients have been described. In our study, we present five cases of 4p16.3 deletion with different origins and mechanisms of formation.

A Case of Wolf-Hirschhorn Syndrome with Early Rehabilitation Intervention from the Neonatal Period

A Case of Wolf-Hirschhorn Syndrome with Early Rehabilitation Intervention from the Neonatal Period

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients.

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Abstract 9544: PRDM16 Loss in 1p36 Deletion Syndrome is Associated With Worse Cardiovascular Outcomes: A Multi-Institutional Registry Study

Introduction: 1p36 deletion syndrome can confer a predisposition to pediatric-onset cardiomyopathy. 1p36 deletion breakpoints are variable and can delete PRDM16 , a cardiac transcription factor. Early studies suggest PRDM16 loss may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. Hypothesis: Deletion of PRDM16 in 1p36 deletion syndrome (“ PRDM16 deleted”) is associated with the development of cardiomyopathy and adverse cardiovascular outcomes. Methods: This registry study included Duke University Hospital, Texas Children’s Hospital, Primary Children’s Hospital, & Le Bonheur Children’s Hospital. Standard descriptive statistics and Kaplan-Meier estimates were generated. The composite primary outcome was freedom from death, cardiac transplantation, or ventricular assist device (VAD) implantation. A cardiac-specific conditional Prdm16 knockout mouse ( Prdm16 cKO) was generated. Echocardiography, qPCR, and fibrotic staining were performed at 29 weeks. Results: 66 individuals met the inclusion criteria of 1p36 deletion syndrome and at least one clinical encounter. Among individuals with PRDM16 deleted, 37.9% developed cardiomyopathy versus 4.3% of individuals with PRDM16 not deleted (p=0.09). The most common cardiomyopathies in individuals with PRDM16 deleted were LVNC (27.6%) and DCM (13.8%). Individuals with PRDM16 deleted had a 65% probability of developing systolic dysfunction by age 18. Notably, PRDM16 deletion was associated with a significantly increased risk of death, cardiac transplant, or VAD (p=0.04) versus those with PRDM16 not deleted. Prdm16 cKO mice exhibited an increased risk of mortality (p=0.05) and decreased ejection fraction (p<0.01). Prdm16 cKO mice demonstrated significantly increased cardiac fibrosis (p<0.0001), and Tgf-β and Nppb mRNA were significantly upregulated (p<0.05). Conclusions: PRDM16 deletion as part of 1p36 deletion syndrome confers a significantly increased risk of cardiac mortality. Murine models of cardiomyocyte Prdm16 loss demonstrate an increased risk of mortality and cardiomyopathy development. Patients with 1p36 deletion syndrome should be assessed for cardiac disease, particularly those with PRDM16 deletions.

Abstract 15313: Hypoglycemia: The Forgotten "H&T" in Cardiac Arrest

Introduction: Hypoglycemia is known to cause cardiac arrhythmias and even sudden cardiac death by inducing oxidative stress, QT prolongation, and myocardial injury. Chromosomal deletion of 1p36 is associated with learning difficulty, progressive renal disease, and cardiomyopathy. To our knowledge, this is the first case of a patient with 1p36 deletion syndrome and end-stage renal disease (ESRD) who developed cardiac arrest due to hypoglycemia. Case Presentation: A 26-year-old female presented to the emergency department with generalized itching, weakness, and progressive dyspnea after missing multiple hemodialysis (HD) sessions. She was admitted for HD and her stay was complicated by an episode of coffee-ground emesis and she was nil per oral (NPO) for an endoscopy. That night, the patient became bradycardic and had a cardiac arrest with pulseless electrical activity (PEA). Fingerstick blood glucose was undetectable during resuscitation and ROSC was achieved instantaneously after dextrose administration. The patient had no history of diabetes and was refusing glucose checks while NPO. She had a remarkable neurological recovery post-cardiac arrest. However, her glucose levels remained persistently low despite maximally tolerated feeds. An extensive workup for persistent hypoglycemia including peptide C levels, hba1c, and insulin level were within normal limits. Her cortisol level was appropriately raised. CT scan of the head performed was normal. Cardiac catheterization revealed no coronary artery disease. Discussions: Hypoglycemia was removed from the Advanced Cardiovascular Life Support (ACLS) algorithm as a reversible cause of cardiac arrest in 2010. Our case is a reminder of a life-threatening yet quickly reversible cause of cardiac arrest. Conclusions: ESRD increases the risk of hypoglycemia due to decreased insulin clearance and must be carefully monitored while NPO. Physicians have to be aware that routine dextrose administration during cardiac resuscitation does not improve survival and neurological outcomes.

Tumor-augmenting Effect of Histone Methyltransferase WHSC1 on Colorectal Cancer Via Epigenetic Upregulation of TACC3 and PI3K/Akt Activation

Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is a histone methyltransferase which is frequently expressed in an aberrant manner in tumors, but its specific roles and targets in colorectal cancer (CRC) remain unclear. Expression of WHSC1 in CRC tissues and cells was examined by RT-qPCR, immunohistochemistry and immunoblot assays. WHSC1 was knocked down in CRC cells to examine its effect on cell proliferation, invasiveness, migration, epithelial-mesenchymal transition (EMT) activity and apoptosis. The binding between WHSC1 and transforming acidic coiled-coil containing protein 3 (TACC3) was predicted using bioinformatics systems and subsequently validated. In addition, altered expression of TACC3 was introduced into CRC cells to perform functional assays. Stably transfected cells were injected into nude mice to induce xenograft tumors. WHSC1 was highly expressed in CRC tumor tissues and cells with a positive correlation with TACC3 concentration. Specific downregulation of WHSC1 in two CRC cell lines blocked cell proliferation, invasiveness, EMT and migration activity and promoted cell apoptosis. WHSC1 triggers H3K36me2 modification at the level of the TACC3 promoter to induce TACC3 activation. TACC3 suppression similarly blocked the malignant activity of CRC cells, whereas TACC3 restoration in cells counteracted the cancer-suppressive functions of WHSC1 silencing. TACC3 levels were correlated with increased phosphorylation of the PI3K/Akt signaling pathway in cells. Likewise, WHSC1 suppression blocked tumor growth in nude mice. The results of this study revealed TACC3 as a target of WHSC1 in CRC that is positively correlated with PI3K/Akt pathway activation and tumor development.

Gene mutations and chromosomal abnormalities in syndromes with tooth agenesis.

This study aims to review the pathogenic mechanisms and clinical manifestations in syndromes with tooth agenesis (TA). Online Mendelian Inheritance in Man and PubMed databases were searched for a comprehensive review. Previous publications reported complicated aetiologies of syndromic TA. Gene mutations in conserved signalling pathways (WNT, EDA, SHH, FGF, and TGF-β/BMP) and crucial molecules (PAX9, PIXT2, IRF6, the p53 family, and subunits of RNA polymerase III) are the main causes of syndromic TA. In the process of odontogenesis, antagonistic or synergistic interactions are demonstrated in patients and murine models. Mutations in some genes (WNT10A, WNT10B, AXIN2, ANTXR1, MSX1, EDA, EDAR, and EDARADD) can result in both syndromic and isolated TA. In addition, chromosomal anomalies are also responsible for syndromic TA (Down syndrome, Wolf-Hirschhorn syndrome, Williams syndrome, and Pierre Robin sequence). The causes and manifestations of syndromic TA are highly complex, and this constitutes a clinical challenge. Mutations in signalling pathways and crucial molecules as well as chromosomal anomalies are responsible for syndromic TA. And there are overlaps between the causative genes of syndromic and isolated TA.

The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST).

Cri du chat syndrome patients have DNA methylation changes in genes linked to symptoms of the disease

BackgroundCri du chat (also called 5p deletion, or monosomy 5p) syndrome is a genetic disease caused by deletions of various lengths in the short (p) arm of chromosome 5. Genetic analysis and phenotyping have been used to suggest dose-sensitive genes in this region that may cause symptoms when a gene copy is lost, but the heterogeneity of symptoms for patients with similar deletions complicates the picture. The epigenetics of the syndrome has only recently been looked at with DNA methylation measurements of blood from a single patient, suggesting epigenetic changes in these patients. Here, we conduct the deepest epigenetic analysis of the syndrome to date with DNA methylation analysis of eight Cri du chat patients with sibling- and age-matched controls.ResultsThe genome-wide patterns of DNA methylation in the blood of Cri du chat patients reveal distinct changes compared to controls. In the p-arm of chromosome 5 where patients are hemizygous, we find stronger changes in methylation of CpG sites than what is seen in the rest of the genome, but this effect is less pronounced in gene regulatory sequences. Gene set enrichment analysis using patient DNA methylation changes in gene promoters revealed enrichment of genes controlling embryonic development and genes linked to symptoms which are among the most common symptoms of Cri du chat syndrome: developmental delay and microcephaly. Importantly, this relative enrichment is not driven by changes in the methylation of genes on chromosome 5. CpG sites linked to these symptoms where Cri du chat patients have strong DNA methylation changes are enriched for binding of the polycomb EZH2 complex, H3K27me3, and H3K4me2, indicating changes to bivalent promoters, known to be central to embryonic developmental processes.ConclusionsFinding DNA methylation changes in the blood of Cri du chat patients linked to the most common symptoms of the syndrome is suggestive of epigenetic changes early in embryonic development that may be contributing to the development of symptoms. However, with the present data we cannot conclude about the sequence of events between DNA methylation changes and other cellular functions—the observed differences could be directly driving epigenetic changes, a result of other epigenetic changes, or they could be a reflection of other gene regulatory changes such as changed gene expression levels. We do not know which gene(s) on the p-arm of chromosome 5 that causes epigenetic changes when hemizygous, but an important contribution from this work is making the pool of possible causative genes smaller.

Severity Scoring Cutoff for MLPA and Its Diagnostic Yield in 332 North Indian Children with Developmental Delay.

Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.

Epileptic encephalopathy caused by 1p36 deletion: literature review and case series

1p36 deletion syndrome (OMIM: 607872) is an autosomal dominant disease caused by a terminal deletion of the short arm of chromosome 1, characterized by specific craniofacial dysmorphism, delayed speech development and epilepsy. The severity of epilepsy is related to the size of the mutation.Objective: to study the clinical and electroencephalographic picture of the disease.We have analyzed 3 cases (male patients from 2 to 6 years old), including anamnesis of life and disease, electroencephalography data in dynamics and genetic analysis data.All three patients are united by a combination of epilepsy, mental retardation and cerebral palsy-like movement disorders. The epilepsy manifestations varied from severe with absolutely pharmacoresistant epileptic spasms (cases 1 and 2) to mild course with febrile seizures only (case 3). This is probably due to the presence of a shorter mutation in patient 3. Cases 1 and 2 had epileptic encephalopathy, epilepsy with continuing epileptiform discharges on the EEG and a gross delay in speech and mental development. These patients could not speak and not understand the speech addressed, do not follow instructions. Patient 3’ self-care and play activities are developed by age, speech understanding is fully formed, but there is a complete absence of expressive speech.1p36 deletion syndrome is a developmental and epileptic encephalopathy.

Wolf-Hirschhorn syndrome with intrauterine growth restriction in a fetus: A case report

Introduction: Wolf-Hirschhorn syndrome (WHS), a genetic syndrome caused by deletion of the short arm of chromosome 4 (4p), is clinically characterized by “Greek warrior helmet” facial appearance, growth retardation, intellectual disability, seizures, skeletal anomalies, congenital cardiovascular defects, and other systemic defects. The severity of the WHS phenotype is related to the size of the missing 4p terminal fragment. In this article, we report and analyze a case of atypical WHS manifestations that revealed a 21-Mb deletion of the 4p terminal fragment in prenatal amniotic fluid examination by copy number variation sequencing (CNV-seq). Patient concerns: In our case, the fetal ultrasound results presented with intrauterine growth restriction and ocular hypertelorism and were characterized by atypical manifestations such as persistent left superior vena cava, nuchal fold thickness, and extrahepatic portosystemic shunt at 21 + 6 weeks of gestational age. Diagnosis: A fetus with WHS was detected by noninvasive prenatal screening and further diagnosed by chromosome karyotype analysis and CNV-seq. Interventions: After genetic counseling, the couple opted to terminate her pregnancy. Outcomes: Cytogenetic examination of the fetus revealed karyotype 46,XX,del(4)(p15.3). The CNV results showed a 21-MB deletion at the 4p16.3-p15.31 locus. Lessons: The WHS phenotype is atypical in fetuses. Prenatal molecular genetic testing combined with ultrasound screening is an effective method for diagnosing fetal WHS and can help clinicians offer subsequent clinical genetic counseling, manage fetal WHS, and guide the next pregnancy.

Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

SummaryLeucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.