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Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.

Peroxisomes are essential organelles involved in lipid metabolisms including plasmalogen biosynthesis and β-oxidation of very long-chain fatty acids. Peroxisomes proliferate by growth and division of pre-existing peroxisomes. The peroxisomal membrane is elongated by Pex11β and then divided by the dynamin-like GTPase, DLP1 (also known as DRP1 encoded by DNM1L gene), which also functions as a fission factor for mitochondria. Nucleoside diphosphate kinase 3 (NME3) localized in both peroxisomes and mitochondria generates GTP for DLP1 activity. Deficiencies of either of these factors induce abnormal morphology of peroxisomes and/or mitochondria, and are associated with central nervous system dysfunction. To investigate whether the impaired division of peroxisomes affects lipid metabolisms, we assessed the phospholipid composition of cells lacking each of the different division factors. In fibroblasts from the patients deficient in DLP1, NME3, or Pex11β, docosahexaenoic acid (DHA, C22:6)-containing phospholipids were found to be decreased. Conversely, the levels of several fatty acids such as arachidonic acid (AA, C20:4) and oleic acid (C18:1) were elevated. Mouse embryonic fibroblasts from Drp1- and Pex11β-knockout mice also showed a decrease in the levels of phospholipids containing DHA and AA. Collectively, these results suggest that the dynamics of organelle morphology exert marked effects on the fatty acid composition of phospholipids. This article is protected by copyright. All rights reserved.

To analyze the risk for clinically significant microarray aberrations in pregnancies with polyhydramnios. Data from all chromosomal microarray analyses (CMA) performed due to polyhydramnios between January 2013 and December 2019 were retrospectively obtained from the Ministry of Health Database. The rate of clinically significant (pathogenic and likely pathogenic) CMA findings in isolated and non-isolated polyhydramnios cohorts was compared to a local control group of 5541 fetuses with normal ultrasound, in which 78 (1.4%) abnormal results were demonstrated. Subgroup analyses were performed by the degree of polyhydramnios, week of diagnosis, maternal age, and the presence of additional sonographic anomalies. In the isolated polyhydramnios cohort, 19/623 (3.1%) clinically significant CMA aberrations were noted, a significantly higher rate compared to the control population. However, the risk for abnormal CMA results in the 158 cases with mild polyhydramnios (AFI 25–29.9, or maximal vertical pocket 8–11.9 cm) did not significantly differ from pregnancies with normal ultrasound. Of 119 cases of non-isolated polyhydramnios (most frequently associated with cardiovascular (26.1%) and brain (15.1%) anomalies), 8 (6.7%) abnormal CMA findings were noted, mainly karyotype-detectable. Mild polyhydramnios was not associated with an increased rate of clinically significant microarray results, compared to pregnancies with normal ultrasound. An extensive anatomical sonographic survey should be performed in pregnancies with polyhydramnios, with consideration of fetal echocardiography.

Background: NGLY1 is an enigmatic enzyme with multiple functions across a wide range of species. In humans, pathogenic genetic variants in NGLY1 are linked to a variable phenotype of global neurological dysfunction, abnormal tear production, and liver disease presenting the rare autosomal recessive disorder N-glycanase deficiency. We have ascertained four NGLY1 deficiency patients who were found to carry a homozygous nonsense variant (c.1294G > T, p.Glu432*) in NGLY1.Methods: We created an ngly1 deficiency zebrafish model and studied the nervous and musculoskeletal (MSK) systems to further characterize the phenotypes and pathophysiology of the disease.Results: Nervous system morphology analysis has shown significant loss of axon fibers in the peripheral nervous system. In addition, we found muscle structure abnormality of the mutant fish. Locomotion behavior analysis has shown hypersensitivity of the larval ngly1(−/−) fish during stress conditions.Conclusion: This first reported NGLY1 deficiency zebrafish model might add to our understanding of NGLY1 role in the development of the nervous and MSK systems. Moreover, it might elucidate the natural history of the disease and be used as a platform for the development of novel therapies.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

BACKGROUND Isolated populations with high rates of consanguinity and genetic disorders can be found in most parts of the world. The aim of our paper was to highlight the unique challenges faced in genetic counseling for such patients and to discuss the ways to facilitate the difficulties, with an emphasis on the crucial role of electronic medical records (EMR). CASE We report a couple presenting with elevated maternal alpha-fetoprotein in three pregnancies, in which an erroneous diagnosis of epidermolysis bullosa was established in the past and carried along through several years. The live born proband had no evidence of skin disease; however, soon after birth she was diagnosed with congenital nephrotic syndrome. Sequencing of NPHS1 gene yielded a homozygous likely pathogenic genetic variant c.2104G > A (p.Gly702Arg). Population screening performed in the village of residence revealed a carrier frequency of 1-47. This high frequency justified including testing for the founder genetic variant in the national program for population screening. CONCLUSIONS Our report highlights the caution, suspicion and time investment which should be practiced and addressed in genetic counseling of high-risk isolated populations. Using EMR may facilitate reaching the correct diagnosis, enable accurate genetic counseling and provide information for decision-making to the couples, as well as "save" a large community from devastating diseases.

BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown.METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology.RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability.CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.

Inherited liver diseases may present in infancy as cholestatic jaundice progressing to severe hepatic dysfunction. Congenital cytomegalovirus (cCMV) infection may initially involve the liver, yet in otherwise healthy hosts rarely leads to long-term hepatic disease. We report a series of three patients, diagnosed with hereditary liver diseases: progressive familial intrahepatic cholestasis (PFIC) type IV, alpha 1 anti-trypsin deficiency (A1ATD) and Alagille syndrome (ALGS), who were also diagnosed with cCMV infection. All patients were treated with valgancilovir for symptomatic cCMV infection (6-12 months), followed by suppressive dosing in the 2 patients with PFIC and A1ATD. Following 15-24 months of follow-up - the patients with PFIC and A1ATD developed severe liver failure, and the third had ongoing cholestatic disease with stable synthetic function. We propose a significant contribution of cCMV infection to the course of the inherited primary disease, possibly leading to further compromise of the liver. We recommend screening patients with inherited liver disease for cCMV, and considering anti-viral treatment with valganciclovir to delay hepatic disease progression.

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient’s fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient’s cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

Introduction Fetal echogenic bowel is a frequent sonographic finding, demonstrated in about 1% of pregnancies. The advised evaluation of fetal echogenic bowel includes maternal serology, genetic testing for cystic fibrosis, detailed sonographic anatomic survey, and invasive prenatal testing for fetal chromosomal aberrations. The objective of our study was to evaluate the risk for clinically significant chromosomal microarray analysis (CMA) findings in pregnancies with isolated echogenic bowel. Methods Data from all CMA analyses performed due to isolated echogenic bowel reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal microarray findings to the control population, based on a systematic review of 9272 pregnancies and a large local cohort of 5541 fetuses with normal ultrasound, undergoing CMA testing due to maternal request. Results Of 103 CMA analyses performed due to isolated echogenic bowel, two (1.94%) pathogenic findings were detected (47,XYY and 16p11.2 duplication). This risk was not significantly elevated compared to the control groups. In addition, three variants of unknown significance were demonstrated. Conclusions To our best knowledge, our study is the first report describing the rate of clinically significant copy number variants in pregnancies with isolated echogenic bowel. According to our results, it seems that pregnancies with isolated echogenic bowel do not have an increased risk for abnormal CMA compared to fetuses with no evidence of sonographic anomalies. Our findings suggest that the consideration to perform CMA analysis in such pregnancies should not differ from any pregnancy with normal ultrasound.

STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1-related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1-syntaxin 1A complex. Comparison of the interaction interfaces of the wild-type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1-syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function.

Accumulation of lipid peroxides causes membrane damage and cell death. Glutathione peroxidase 4 (GPX4) acts as a hydroperoxidase which prevents accumulation of toxic oxidized lipids and blocks ferroptosis, an iron-dependent, non-apoptotic mode of cell death. GPX4 deficiency causes Sedaghatian-type spondylo-metaphyseal dysplasia (SSMD), a lethal autosomal recessive disorder, featuring skeletal dysplasia, cardiac arrhythmia and brain anomalies with only three pathogenic GPX4 variants reported in two SSMD patients. Our objective was to identify the underlying genetic cause of neonatal death of two siblings presenting with hypotonia, cardiorespiratory failure and SSMD. Whole exome sequencing (WES) was performed in DNA samples from two siblings and their parents. Since "critical samples" were not available from the patients, DNA was extracted from dry blood spots (DBS) retrieved from the Israeli newborn-screening center. Sanger sequencing and segregation analysis followed the WES. Homozygous novel GPX4 variant, c.153_160del; p.His52fs*1 causing premature truncation of GPX4 was detected in both siblings; their parents were heterozygotes. Segregation analysis confirmed autosomal recessive inheritance. This report underscores the importance of DBS WES in identifying the genes and mutations causing devastating rare diseases. Obtaining critical samples from a dying patient is crucial for enabling genetic diagnosis.

Background With the continuing decrease in cost of whole genome sequencing (WGS), we have already approached the point of inflection where WGS testing has become economically feasible, facilitating broader access to the benefits that are helping to define WGS as the new diagnostic standard. WGS provides unique opportunities for detection of structural variants; however, such analyses, despite being recognized by the research community, have not previously made their way into routine clinical practice. Results We have developed a clinically validated pipeline for highly specific and sensitive detection of structural variants basing on 30X PCR-free WGS. Using a combination of breakpoint analysis of split and discordant reads, and read depth analysis, the pipeline identifies structural variants down to single base pair resolution. False positives are minimized using calculations for loss of heterozygosity and bi-modal heterozygous variant allele frequencies to enhance heterozygous deletion and duplication detection respectively. Compound and potential compound combinations of structural variants and small sequence changes are automatically detected. To facilitate clinical interpretation, identified variants are annotated with phenotype information derived from HGMD Professional and population allele frequencies derived from public and Variantyx allele frequency databases. Single base pair resolution enables easy visual inspection of potentially causal variants using the IGV genome browser as well as easy biochemical validation via PCR. Analytical and clinical sensitivity and specificity of the pipeline has been validated using analysis of Genome in a Bottle reference genomes and known positive samples confirmed by orthogonal sequencing technologies. Conclusion Consistent read depth of PCR-free WGS enables reliable detection of structural variants of any size. Annotation both on gene and variant level allows clinicians to match reported patient phenotype with detected variants and confidently report causative finding in all clinical cases used for validation. Electronic supplementary material The online version of this article (10.1186/s12864-019-5866-z) contains supplementary material, which is available to authorized users.

OBJECTIVE The aim of the study was to study the associations between localized provoked vulvodynia (LPV) and several single-nucleotide polymorphisms (SNPs) in the transient receptor potential vanilloid type 1 (TRPV1), nerve growth factor (NGF), and the heparanase (HPSE) genes. MATERIALS AND METHODS Prevalence of SNPs among 65 women with moderate or severe primary LPV (initial symptoms occur with first provoking physical contact) and 126 healthy, ethnically matched controls was analyzed in an observational case-control study. Each participant answered a questionnaire addressing familial LPV occurrence and comorbid pain conditions. RESULTS Familial occurrences of LPV, temporomandibular joint (TMJ) symptoms, recurrent vaginitis, and irritable bowel syndrome were significantly higher among LPV women than healthy controls. Genotyping analyses revealed a novel, statistically significant high prevalence of polymorphism c.945G>C (rs222747) of TRPV1 and a SNP in the promoter region of NGF (rs11102930) in LPV women compared with controls. A logistic regression model for rs222747 and rs11102930 frequent alleles indicates significant LPV association within the entire study group and Ashkenazi Jewish women, respectively. Comparison of pain conditions with frequent alleles showed the rs222747 "CC" genotype of TRPV1 associated with women with TMJ, recurrent vaginitis, and LPV. CONCLUSIONS Our results suggest novel genetic susceptibility to primary LPV associated with specific alleles in genes TRPV1 and NGF and propose the rs222747 "C" allele of TRPV1 as a common genetic predisposition for other pain syndromes.

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex., C.A.P., M.J.S., P.R.-G. and M.M. were supported by the core funding from the Medical Research Council, UK (MC_U105697135 and MC_UU_00015/4). J.V.H. and M.W.F. were supported by Miracles for Mito, the Children’s Hospital Colorado Foundation and University of Colorado Foundation. This work was supported by Telethon Foundation, Italy grant GGP15041 to C.D. This work was also supported by Instituto de Salud Carlos III, http://www.isciii.es/, PI13/00556 to R.G.; FEDER funds from the E.U. to R.G. and Instituto de Salud Carlos III, http://www.isciii.es/, PI16/00789 to R.G. and M.A.F-M. P.R.-G. was supported by Fundação para a Ciência e a Tecnologia (PD/BD/105750/2014).

Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNAGln, that impairs mitochondrial translation and presents with cardiomyopathy., Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients’ fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

Objective To examine the risk for clinically significant chromosomal microarray analysis (CMA) among fetuses with apparently isolated horseshoe kidney. Methods Data from all CMA analyses performed due to isolated horseshoe kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained from a computerized database. Risk estimation was performed comparing the rate of abnormal CMA findings to the general population, based on a systematic review encompassing 9272 pregnancies with normal ultrasound, and local data cohort of 5541 pregnancies undergoing CMA due to maternal request. Results Of 82 pregnancies with isolated horseshoe kidney, one loss-of-copy-number variant compatible with 16p13.11 microdeletion syndrome was demonstrated (1.2%). In addition, two variants of unknown significance (VOUS) were detected (2.4%). The relative risk for pathogenic CMA findings among pregnancies with isolated single horseshoe kidney was not significantly different from the control population (1.03–1.39%). Discussion To our best knowledge, our study is the first report describing the rate of clinically significant CMA findings in fetuses with isolated horseshoe kidney. The detection of one pathogenic CMA findings in our cohort implies that the value of CMA analysis in such pregnancies is similar to the general population.

The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial-skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription-coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease.

Background Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. Methods The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. Results The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A ( Vps37A ) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. Conclusions The authors provide evidence for the involvement of Vps37A , a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Mammary-digital-nail syndrome is a novel phenotypic association consisting of anonychia onychodystrophy with hypoplasia or absence of distal phalanges in males and females, accompanied by juvenile hypertrophy of the breast in affected females. This newly described genetic trait presents an autosomal dominant inheritance pattern, with either reduced penetrance or germ-line mosaicism. Analysis of the pedigree, linkage studies followed by a genome-wide screen and by haplotype analysis defined the locus for the phenotype within a 12 cM (4.3 Mb) interval on chromosome 22q12.3-13.1. This chromosomal region has not been implicated before in genetic disorders of the mammary tissue or limbs. These data suggest a possibly novel signaling pathway affecting the organogenesis of limbs and mammary glands in humans.

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C--G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients.

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8–16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a DSCR1 and DYRK1A , or APP , in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.

Whole exome sequencing (WES) is a powerful technique for identifying sequence changes in the human genome. The goal of this study was to delineate the genetic defects in patients with inherited retinal diseases (IRDs) using WES. WES was performed on 90 patient DNA samples from 68 families and 226 known genes for IRDs were analyzed. Sanger sequencing was used to validate potential pathogenic variants that were also subjected to segregation analysis in families. Thirty-three causative mutations (19 novel and 14 known) in 25 genes were identified in 33 of the 68 families. The vast majority of mutations (30 out of 33) have not been reported in the Israeli and the Palestinian populations. Nine out of the 33 mutations were detected in additional families from the same ethnic population, suggesting a founder effect. In two families, identified phenotypes were different from the previously reported clinical findings associated with the causative gene. This is the largest genetic analysis of IRDs in the Israeli and Palestinian populations to date. We also demonstrate that WES is a powerful tool for rapid analysis of known disease genes in large patient cohorts.

Diagnosis and treatment of an anuric premature infant with severe respiratory compromise and a normal renal ultrasound (US), is a difficult task that requires a multidisciplinary approach. A 29-week gestation premature male infant, born after 5 weeks of worsening oligohydramnios, was ventilated for respiratory distress and remained anuric. Intensive clinical investigations and pediatric nephrology consultation that predicted very poor prognosis were followed by progressive renal failure, electrolyte imbalance, respiratory failure, ventricular arrhythmia, and finally cardiac arrest and death on day 5. In view of the predicted poor outcome, and after discussion with the parents, a decision was made not to start peritoneal dialysis (PD), and to offer only palliative therapy, with comfort care alone. Pre and postnatal diagnosis lead, in this case, to an ethical challenge that focuses on the question of futility. Copyright © 2006 John Wiley & Sons, Ltd.

Objective: Juvenile (virginal) hypertrophy of the breast (JHB) is a relatively rare condition leading to gigantomastia in peripubertal females. The pathology is limited usually to the breast, with otherwise normal growth and development and without any other deformities. The rapid growth of the breast (bilateral or unilateral) in adolescent girls leads to significant physical and psychological difficulties. This gigantomastia is treated surgically by breast reduction or mastectomy and its modification. Familial JHB was described only once in the literature, and its etiology is unknown. Results We report here on a familial pattern of juvenile hypertrophy of the breast accompanied by congenital anonychia. To the best of our knowledge, this is the first report of such a presentation. Our study dealt with four members of the same family, related through their fathers, enduring congenital anonychia of hands and feet with no functional limitation and who showed rapid uncontrolled breast enlargement in prepubertal age. This was severe enough to cause the curtailment of their social activity and cessation of schooling. The mothers of all four patients had normal breasts and nails, whereas their fathers had anonychia. The genetic basis for the association between the two clinical findings is yet to be determined. Conclusion The four girls underwent breast reduction surgery.

Summary. The grey platelet syndrome (GPS) is a bleeding disorder of unknown aetiology with phenotypic and genetic heterogeneity. Affected patients exhibit macrothrombocytopenia, decreased alpha-granule content and, sometimes, myelofibrosis. We used microarray technology to investigate changes in gene expression that might reveal mechanisms involved in GPS. The expression of 4900 unique genes and expressed sequence tags was evaluated in fibroblasts from a GPS patient; normal fibroblasts provided the reference standard. Genes that were differentially regulated in the GPS cells were categorized into gene clusters based upon similarity/differences of expression differences. The results showed that genes with functional similarities clustered together. This analysis revealed significant upregulation of selected biological processes involving the production of cytoskeleton proteins, including fibronectin 1, thrombospondins 1 and 2, and collagen VI α. These genes appear to play a role in the pathogenesis of GPS. Indeed, Northern blot analyses confirmed that fibronectin, thrombospondin and matrix metalloprotease-2 were overexpressed in GPS fibroblasts compared with normal fibroblasts. Moreover, immunohistochemistry studies revealed robust fibronectin staining in GPS fibroblasts compared with normal ones. Our findings support the feasibility of using cDNA microarray techniques to detect distinctive and informative differences in gene expression patterns relevant to GPS, and suggest that the molecular basis for myelofibrosis in GPS involves upregulation of cytoskeleton proteins.

The Muslim Circassian community in Israel represents a unique ethnic community that has never been genetically and medically studied. One hundred and fifty-three randomly selected individuals (91 men and 62 women, ages 35 and older), both healthy or with a history of cardiovascular disease (14 men and 7 women), were studied in a cross-sectional descriptive study for mutations in three genes known to be associated with hypercoagulation. Their medical records were reviewed for risk factors and history of cardiovascular disease (CVD) and thromboembolic events. The mutation FV 1691G --> A in the gene for factor V (FV 1691G --> A), the mutation MTHFR 677C --> T in the gene 5,10-methylenetetrahydrofolate reductase, and the allele G20210A in the gene for prothrombin (PT 20210G --> A) were studied. The mutation FV 1691G --> A was observed in a heterozygous form in 1.3% of 153 studied individuals, while the PT 20210G --> A allele was identified in a heterozygous form in 6.5%. No individual was found homozygous for either of these two mutations. The MTHFR C677T mutation was present in 42.8% of the studied population in a heterozygous form and in 8.6% in a homozygous form. Serum homocysteine, folate, and B12 levels were studied among individuals heterozygous and homozygous for the MTHFR C677T mutation. There was no significant difference in the prevalence of all three mutations between individuals affected with CVD or other forms of thromboembolic disease and healthy individuals. This is the first report of a medical condition and its genetic background among Circassians. The high prevalence of CVD among Circassians was found to be etiologically unrelated to the three mutations studied in the genes for factor V, MTHFR, and prothrombin.

Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder that is characterized by large platelets that lack α-granules. Here we show that mutations in NBEAL2 (neurobeachin-like 2), which encodes a BEACH/ARM/WD40 domain protein, cause GPS and that megakaryocytes and platelets from individuals with GPS express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.

Gray platelet syndrome (GPS) is a disorder characterized by thrombocytopenia and large platelets that lack alpha granules and their contents. We describe two siblings with GPS who are members of a Moslem Bedouin genetic isolate. The children, an 8-year-old girl and a 5-year-old boy, had characteristic pale blue platelets lacking alpha granules on electron microscopy. Platelet aggregation studies were normal. The girl underwent a bone marrow aspiration and biopsy which showed mild myelofibrosis and extensive emperipolesis, i.e., the passage of other hematopoietic cells through megakaryocytes. Both children lacked high-molecular-weight multimers of von Willebrand factor (vWF) and had reduced activity and antigens of vWf. Platelet activation was approximately normal when ADP was employed as agonist, but significantly impaired using the thrombin receptor-activating peptide (TRAP). These findings are explained in light of the mechanism of action of each agonist. In addition, we propose that the emperipolesis was caused by increased P-selectin in megakaryocytes, and resulted in release of fibroblastic growth factors, explaining the myelofibrosis. The detailed description of these cases provides a basis for future differentiation of the various types of GPS, and for our current attempts to isolate the gene causing GPS in this genetic isolate.

Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and/or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester. The identification of mutations in the genes encoding keratins K5 and K14 as the cause of EBS opens up the possibility of much earlier diagnosis of the disease. We report here four cases in which prenatal testing was performed. In three of the cases the genetic lesions were unknown at the start of the pregnancy, requiring the identification of the causative mutation prior to testing fetal DNA. In two of the four cases novel mutations were identified in K14 and in the two remaining families, a previously identified type of mutation was found. Fetal DNA, obtained by chorionic villus sampling or amniocentesis, was analysed for the identified mutations. Three of the DNA samples were found to be normal; a mutant K14 allele was identified in the fourth case and the pregnancy was terminated. These results demonstrate the feasibility of DNA-based prenatal testing for EBS in families where causative mutations can be found. Copyright © 2000 John Wiley & Sons, Ltd.

A retrospective population study was conducted to determine the carrier frequencies of recently identified mutations in Oriental Jewish cystic fibrosis patients.Data were collected from 10 medical centers that screened the following mutations: two splice site mutations-3121-1GA and 2751 + 1insT-and one nonsense mutation-the Y1092X in Iraqi Jews. One missense mutation, I1234V, was screened in Yemenite Jews.A total of 2499 Iraqi Jews were tested for one, two, or all three mutations. The 3121-1GA, Y1092X, and 2751 + 1insT mutations had a carrier frequency of 1:68.5, 1:435, and 0, respectively. In 1435 Yemenite Jews screened, I1234V had a carrier frequency of 1:130.The 0.84% allele frequency of the three Iraqi founder mutations falls within the Israeli Society of Medical Geneticists' inclusion criteria for screening of 1:60 carrier frequency; hence, Iraqi Jews were added to the carrier screening policy with a panel including the three Iraqi founder mutations in addition to the five Ashkenazi mutations previously detected in Eastern Jews. 2751 + 1insT that was detected in patients only was included in the screening panel to increase the detection rate. I1234V does not meet the inclusion criteria but is now offered on a diagnostic basis and can be added to the screening panel for individuals whose mixed origin includes Yemenite, in addition to protocol-recommended origins. This study demonstrates the dynamic modifications of the Israeli carrier cystic fibrosis screening protocol based on newly detected founder mutations in a large cohort, taking into account mutation impact and intercommunal admixture.

Two of DNA's worst enemies, ultraviolet light and chemical carcinogens, can cause damage to the molecule by mutating individual nucleotides or changing its physical structure. In most cases, genomic integrity is restored by specialized suites of proteins dedicated to repairing specific types of injuries. One restoration mechanism, called nucleotide excision repair (NER), recruits and coordinates the services of 20-30 proteins to recognize and remove structure-impairing lesions, including those induced by ultraviolet (UV) light. Mutations in a gene that encodes a protein from the NER machinery might cause a wide variety of rare inherited human disorders. Sun sensitivity, cancer, developmental retardation, neurodegeneration and premature aging characterize these syndromes. Identification of the causative genes and proteins in affected families in Israel allowed us to establish accurate molecular diagnosis of couples at risk, and provide them with better genetic counseling.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease with multi-organ involvement. The clinical manifestations usually start at infancy and develop during the first and second decades of life; infantile-onset diarrhea may be the earliest clinical manifestation of CTX. Additional clinical manifestations are juvenile cataracts, tendon xanthomas, and multiple progressive neurological symptoms. Systemic manifestations that are often found include osteoporosis, heart involvement and premature arteriosclerosis. CTX is caused by mutations in the sterol 27 hydroxylase gene (CYP27) on chromosome 2q35-qter, which is responsible for conversion of cholesterol to cholic and chenodeoxycholic acid. Reduced synthesis of cholic and chenodeoxycholic acid results in failed feedback inhibition of cholesterol production, which in turn leads to increased serum cholestanol concentration and elevated urinary bile alcohols. Early treatment with chenodeoxycholic acid (CDCA) prevents the clinical symptoms and prevents deterioration. Although CTX is rare world wide, genetic islands of high frequency have been reported. In this review we would like to familiarize the reader with this fatal inborn error of metabolism that is possibly under-diagnosed and is preventable once recognized and treated.

Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is a rare, autosomal recessive neurologic disorder, characterized by absence of reaction to painful stimuli, mental retardation, self- mutilating behavior, anhidrosis, and recurrent episodes of hyperthermia. Mutations in the neurotrophic tyrosine kinase receptor 1, a receptor phosphorylated by nerve growth factor, have been documented in diverse ethnic groups. We identified the same novel nonsense mutation in two unrelated families of Moroccan Jewish descent, each with two affected siblings. This possible founder mutation may trace to the rural Jewish village in southern Morocco from where both these families originated. Genetic screening for the causative mutation among 300 unrelated Moroccan Jews did not reveal carriers for the causative mutation, thus excluding high risk for CIPA in this ethnic subpopulation.

Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (

Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society.

Purpose: The Druze community is characterized by consanguinity and endogamy, and by reluctance to genetic testing and technological interventions for the prevention of birth defects. Multiple patients with four rare and severe inborn errors of metabolism cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified in an isolated Druze village in northern Israel. The aims of this study were to identify couples at risk for four inherited diseases, and to prevent birth defects in a community presenting religious and cultural obstacles to genetic testing. Methods: A genetic screening and counseling program in a high-risk community. Results: The 1425 residents who attended group genetic counseling sessions between 2003 and 2007 consented to genetic testing. We identified 217 carriers for either one or two disease causing mutations. High carrier frequencies for cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified as 1:11, 1:21, 1:41, and 1:95, respectively. Fifty-eight percent (125) of the carriers' spouses agreed to genetic counseling and testing. Ten couples at risk for affected offspring were identified and offered prenatal genetic counseling and diagnosis. Conclusions: The genetic screening program, the first of its kind reported in a Druze community, was well received. We expect this program to increase awareness of genetic counseling, to contribute to disease prevention, and to serve as a model for other isolated communities.

Cockayne syndrome (CS) (OMIM #133540) is a rare autosomal recessive disease characterized by severe growth and developmental retardation, progressive neurological dysfunction and symptoms of premature aging. The underlying cause of the disease is a defect in transcription-coupled DNA repair, specifically the nucleotide excision repair (NER) pathway. To date, about half of the reported CS cases have an altered cellular response to UV resulting from mutations in either the CSA or the CSB genes. We have identified a large, highly consanguineous, Druze kindred descended from a single ancestor, with six CS cases. All six of them presented with the congenital severe phenotype that includes severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, and kyphosis. They had no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription-coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in 1:15 healthy individuals from the same village, indicating an extremely high carrier frequency. Identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village.

Contains fulltext : 69027.pdf (Publisher’s version ) (Closed access) The rare autosomal recessive disorder pyridoxine 5'-phosphate oxidase (PNPO) deficiency is a recently described cause of neonatal and infantile seizures. Clinical evaluation, and biochemical and genetic testing, were performed on a neonate with intractable seizures who did not respond to anticonvulsant drugs and pyridoxine. Sequencing of the PNPO gene revealed a novel homozygous c.284G>A transition in exon 3, resulting in arginine to histidine substitution and reduced activity of the PNPO mutant to 18% relative to the wild type. This finding enabled molecular prenatal diagnosis in a subsequent pregnancy, accurate genetic counseling in the large inbred family, and population screening.

Mutations in MRAP, an interacting partner of the ACTH receptor, have been shown recently to cause familial glucocorticoid deficiency (FGD) in kindreds with confirmed FGD and no ACTH receptor mutations.We describe a Jewish-Ethiopian family with FGD caused by a novel MRAP mutation.Our index patient presented at the age of 19 months with hypocortisolism, severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Before the definite diagnosis was made, a female sibling was born in another hospital and succumbed during the neonatal period due to sepsis and adrenal crisis.DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient. The DAX-1, ACTH receptor (MC2R), and MRAP genes were analyzed.The index patient was diagnosed with FGD and was found to be homozygous for a novel MRAP mutation, a seven-base deletion in exon 3 of the MRAP gene. This deletion causes a frame shift, resulting in a stop codon after 23 amino acids (L31X). Postmortem analysis of fibroblasts obtained from the female patient revealed that she harbored the same mutation.This is the first report of MRAP mutations after the recent identification of the gene. Whether the novel MRAP mutation described by us is associated with a particularly severe phenotype remains to be investigated.

The grey platelet syndrome (GPS) is a bleeding disorder of unknown aetiology with phenotypic and genetic heterogeneity. Affected patients exhibit macrothrombocytopenia, decreased alpha-granule content and, sometimes, myelofibrosis. We used microarray technology to investigate changes in gene expression that might reveal mechanisms involved in GPS. The expression of 4900 unique genes and expressed sequence tags was evaluated in fibroblasts from a GPS patient; normal fibroblasts provided the reference standard. Genes that were differentially regulated in the GPS cells were categorized into gene clusters based upon similarity/differences of expression differences. The results showed that genes with functional similarities clustered together. This analysis revealed significant upregulation of selected biological processes involving the production of cytoskeleton proteins, including fibronectin 1, thrombospondins 1 and 2, and collagen VI alpha. These genes appear to play a role in the pathogenesis of GPS. Indeed, Northern blot analyses confirmed that fibronectin, thrombospondin and matrix metalloprotease-2 were overexpressed in GPS fibroblasts compared with normal fibroblasts. Moreover, immunohistochemistry studies revealed robust fibronectin staining in GPS fibroblasts compared with normal ones. Our findings support the feasibility of using cDNA microarray techniques to detect distinctive and informative differences in gene expression patterns relevant to GPS, and suggest that the molecular basis for myelofibrosis in GPS involves upregulation of cytoskeleton proteins.

Six families with prolidase deficiency (PD) and chronic lung disease are reported, a previously unrecognized association. In one family with a classic cystic fibrosis (CF) phenotype, no evidence for CF Transmembrane Conductance Regulator (CFTR)-related mutations could be found. Chronic lung disease and CFTR-mutation negative CF may be associated with PD.

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.