A case of Ververi-Brady syndrome due to QRICH1 loss of function and the literature review.

Ververi-Brady syndrome (VBS), first reported in 2018, is characterized by intellectual disability, speech delay, and mild dysmorphic facial features. VBS has been linked to de novo loss-of-function variants in the glutamine-rich protein 1 (QRICH1) on chromosome 3p21 and was reported until lately in only five individuals. Four additional cases have just been described substantiating the notion that children with VBS are mildly dysmorphic, mildly to moderately intellectually disabled, have linear growth shortage, are picky eaters, and have notable attention and social behavioral deficits. We describe a new patient and review the clinical and genetic information, on all previously reported VBS cases. The child here reported is noted for maladaptive behavior, sensory hypersensitivity, and slow linear growth. He is mainly hyperactive, distractible, impulsive, and inattentive. His speech, initially delayed, is fair and his verbal comprehension age adequate.

LRRK2, GBA and SMPD1 Founder Mutations and Parkinson's Disease in Ashkenazi Jews.

BACKGROUND/AIM: Parkinson's disease (PD) is associated with mutations in LRRK2, GBA, and SMPD1 genes. We describe the clinical characteristics of PD patients related to their carrier status of the Ashkenazi founder mutations in the aforementioned genes. METHODS: Ashkenazi PD patients (n = 270) were recruited following informed consent, and tested for the founder Ashkenazi mutations in the above genes. Clinical characteristics were compared between carriers and noncarriers. Homozygotes for mutations in GBA or LRRK2, and those who carried mutations in two causative genes were excluded from the analysis. RESULTS: Five (1.85%), 54 (20%), and 22 (8.1%) PD patients carried mutations in SMPD1, GBA or LRRK2, respectively. By post hoc Bonferroni analysis, GBA carriers were singled at a significantly earlier age at diagnosis compared to noncarriers (58.06 ± 10.84 and 62.65 ± 10.86 years, respectively; p = 0.036), and due to bilateral manifestation at diagnosis compared to all other PD groups (n = 8, 15.7% compared to n = 2, 1.1%, respectively; p < 0.001). Other clinical manifestations were comparable between groups. CONCLUSION: Although only GBA mutation carriers, compared to noncarriers, reached statistical significance regarding age at diagnosis, it appears that LRRK2 and SMPD1 mutation carriers may reach significance with larger group numbers.

Latitudinal Clines of the Human Vitamin D Receptor and Skin Color Genes.

The well-documented latitudinal clines of genes affecting human skin color presumably arise from the need for protection from intense ultraviolet radiation (UVR) vs. the need to use UVR for vitamin D synthesis. Sampling 751 subjects from a broad range of latitudes and skin colors, we investigated possible multilocus correlated adaptation of skin color genes with the vitamin D receptor gene (VDR), using a vector correlation metric and network method called BlocBuster. We discovered two multilocus networks involving VDR promoter and skin color genes that display strong latitudinal clines as multilocus networks, even though many of their single gene components do not. Considered one by one, the VDR components of these networks show diverse patterns: no cline, a weak declining latitudinal cline outside of Africa, and a strong in- vs. out-of-Africa frequency pattern. We confirmed these results with independent data from HapMap. Standard linkage disequilibrium analyses did not detect these networks. We applied BlocBuster across the entire genome, showing that our networks are significant outliers for interchromosomal disequilibrium that overlap with environmental variation relevant to the genes' functions. These results suggest that these multilocus correlations most likely arose from a combination of parallel selective responses to a common environmental variable and coadaptation, given the known Mendelian epistasis among VDR and the skin color genes.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome.

OBJECTIVE: To evaluate the efficacy of colchicine in reducing the frequency of attacks in patients with PFAPA. STUDY DESIGN: We conducted a 6-month open label, randomized, controlled study among patients with PFAPA who attend the Pediatric Rheumatology Clinic at the Rambam Medical Center in Israel. A total of 18 patients aged4 -11 years (males:females ratio = 11:7) were randomized into a control group (I, 10 children) and a study group (II, 8 children). Group I was followed for 6 months without any intervention, and group II was initially followed for 3 months and was thereafter treated with colchicine for 3 additional months, according to standard regimen. During the 6-month period of the study the patients and their physician recorded all the episodes of PFAPA in a constructed log. DNA analyses for the 5 common FMF mutations in Israel were performed in 17 out of the 18 patients. RESULTS: The number of episodes during the first 3 months was similar in both groups (group I 3.2 ± 1.5, group II 4.9 ± 2.3; p ≤ 0.12). Group II had significantly less PFAPA attacks in the second period while on colchicine therapy (4.9 ± 2.3 vs. 1.6 ± 1.2; p ≤ 0.01), in opposition to group I, where no difference in the number of attacks was noted between the first and second period of follow-up (3.2 ± 1.5 vs. 2.7 ± 1.5; p = 0.33). Of the 17 patients tested, 8 were carriers for FMF mutations (2 in group I and 6 in group II). CONCLUSION: Colchicine prophylaxis seems to be effective in reducing the number of attacks in PFAPA.

A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema.

BACKGROUND: Primary lymphedema covers around 10% of all lymphedema cases. Most cases segregate as an autosomal dominant trait and rarely manifest autosomal recessive inheritance. Our research aimed to map and ultimately to hunt the mutation that causes hereditary lymphedema in an extended consanguineous Muslim family consisting of several affected individuals. METHODS AND RESULTS: We attempted molecular diagnosis by applying homozygosity mapping and whole genome linkage analysis. A candidate locus of 2.3 Mb located on chromosome 5q35.3 was identified, yielding an overall LOD score of 3.18. This locus has been previously linked to congenital lymphedema, namely by the FLT4 gene. Mutations in FLT4 that were previously described in Muslim-Israeli families were discarded as culprit using sequence analysis. Sanger sequencing the gene revealed a novel missense variant in exon 28 (NM_182925.4: c.3704C>G; p.Ser1235Cys). This variant has perfect segregation within the extended family and was not previously reported in either common or pathogenic variants databases. CONCLUSIONS: Our mutation is the first reported pathogenic variant located outside the tyrosine kinase domains of the VEGFR3 receptor, and the second to portray autosomal recessive inheritance. The homozygous substitution of serine by cysteine at position 1235 affects protein tyrosine kinase activity, possibly through a null effect mechanism rather than a negative dominant effect. Our variant is associated with a mild phenotype, possibly reflecting some residual receptor activity, most probably attributed to the variant's location beyond the TK domains.

Absence of α- and ß-dystroglycan is associated with Walker-Warburg syndrome.

OBJECTIVE: To identify the underlying genetic defect in 5 patients from a consanguineous family with a Walker-Warburg phenotype, together with intracranial calcifications. METHODS: Homozygosity mapping and exome sequencing, followed by Sanger sequencing of the obtained candidate gene, was performed. Expression of the candidate gene was tested by reverse transcription PCR. Patient fibroblasts were converted to myotubes, and the expression and function of dystroglycan was tested by Western blotting. RESULTS: We detected a homozygous loss-of-function frameshift mutation in the DAG1 gene and showed that this mutation results in a complete absence of both α- and ß-dystroglycan. CONCLUSIONS: A loss-of-function mutation in DAG1 can result in Walker-Warburg syndrome and is not embryonic lethal.

Israeli Society of Medical Genetics NIPT Committee Opinion 072013: Non-invasive prenatal testing of cell-free DNA in maternal plasma for detection of fetal aneuploidy.

Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma is a novel approach, designed for detecting common aneuploidies in the fetus. The Israeli Society of Medical Geneticists (ISMG) supports its use according to the guidelines stated herein. The clinical data collected thus far indicate that NIPT is highly sensitive in detecting trisomies 21 and 18, and fairly sensitive in detecting trisomy 13 and sex chromosome aneuploidies. Because false-positive results may occur, an abnormal result must be validated by invasive prenatal testing. At this juncture, NIPT does not replace existing prenatal screening tests for Down syndrome, as these are relatively inexpensive and cost-effective. Nonetheless, NIPT may be offered to women considered to be at high risk for fetal chromosomal abnormalities as early as 10 weeks of gestation. The ISMG states that NIPT should be an informed patient choice, and that pretest counseling regarding the limitations of NIPT is warranted. Women at high risk for genetic disorders not detected by NIPT should be referred for genetic counseling. A normal test result may be conveyed by a relevant healthcare provider, while an abnormal result should be discussed during a formal genetic consultation session.

"I do not want my baby to suffer as I did"; prenatal and preimplantation genetic diagnosis for BRCA1/2 mutations: a case report and genetic counseling considerations.

This article presents the complexity of prenatal genetic diagnosis and preimplantation genetic diagnosis for hereditary breast-ovarian cancer syndrome. These issues are discussed using a case report to highlight the genetic counseling process, together with decision-making considerations, in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries.

Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel.

BACKGROUND: Kohlschutter-Tonz syndrome (KTS; MIM 22675) is a rare autosomal recessive disorder characterized by intellectual impairment, spasticity, epilepsy, and amelogenesis imperfecta. We have recently identified the causative gene and mutation underlying KTS, namely, p.R157X, corresponding to ROGDI c.571C>T, which creates a premature stop codon in ROGDI homolog (Drosophila), a gene of unknown function, in KTS patients of Druze origin. PATIENTS: To better delineate the phenotype of KTS, 16 cases (eight female, eight male), from seven families (five kindreds) originating from a Druze village in Northern Israel, all homozygous for the same deleterious mutation, were investigated. Medical records were reviewed, and a detailed medical history was obtained by interview of parents. RESULTS: Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration. Amelogenesis imperfecta and deficient speech occur in all cases. By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception. CONCLUSIONS: KTS, a genetic disease heralded by convulsions, "yellow teeth," and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration. In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties.

A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred.

Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein.

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study.

BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number <26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (<26, 26-34, and >34 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n=368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted.

Evidence-based recommendations for the practical management of Familial Mediterranean Fever.

AIM: Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues-e.g.: colchicine dosage adjustment, maximum dosage of colchicine in children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings-have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. METHODS: A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. RESULTS: A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. CONCLUSION: This is a first attempt to resolve practical questions in the daily management of FMF patients.

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations.

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome.

Kohlschutter-Tonz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset, and it is characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. In 12 KTS-affected individuals from a Druze village in northern Israel, homozygosity mapping localized the gene linked to the disease to a 586,513 bp region (with a LOD score of 6.4) in chromosomal region 16p13.3. Sequencing of genes (from genomic DNA of an affected individual) in the linked region revealed chr16: 4,848,632 G>A, which corresponds to ROGDI c.469C>T (p.Arg157(∗)). The nonsense mutation was homozygous in all affected individuals, heterozygous in 10 of 100 unaffected individuals from the same Druze community, and absent from Druze controls from elsewhere. Wild-type ROGDI localizes to the nuclear envelope; ROGDI was not detectable in cells of affected individuals. All affected individuals suffered seizures, were unable to speak, and had amelogenesis imperfecta. However, age of onset and the severity of mental and motor handicaps and that of convulsions varied among affected individuals homozygous for the same nonsense allele.

Essential Tremor Prevalence is Low in the Druze Population in Northern Israel.

BACKGROUND: Essential tremor (ET) and Parkinson's disease (PD) are probably the most common movement disorders. As ethnic differences have been reported in ET, we designed the present study to evaluate the prevalence of ET and that of Parkinson's disease (PD) in the Druze villages of northern Israel. METHODS: A two-phase, door-to-door survey was undertaken. Residents aged ≥51 years who agreed to participate and answered "yes" to tremor or PD-related screening questions and 3% of subjects who screened negative were evaluated. Diagnostic criteria for ET were similar to those used in Sicilian and Spanish studies. PD was diagnosed according to Gelb's criteria. RESULTS: The target population consisted of 9,086, the study cohort of 3,980 residents. Tremor was observed in 36 subjects. In 27, the tremor fully met the criteria for ET. The prevalence of ET (age ≥65) was 1.49% (95% CI 0.91-2.07%). PD was diagnosed in 23 subjects. The prevalence of PD (age ≥65) was 1.13 (95% CI 0.62-1.64%). Leucine-rich repeat protein kinase 2 (G2019S mutation) was evaluated in subjects diagnosed with tremor PD and those screened for assessment of the validity of the questionnaire. None carried the mutation. DISCUSSION: The prevalence of ET in the Druze population is low and similar to the prevalence of PD.

Vascular behcet and mutations in thrombogenic genes: methylene tetrahydrofolate reductase, factor V, and prothrombin.

Vasculitis, thrombophlebitis, arterial aneurysms, and occlusions occur in about 25% of patients with Behçet's disease (BD). The common inherited gene defects, factor V (FV) 1691A (Leiden), methylene tetrahydrofolate reductase (MTHFR) 677T, and prothrombin 20210A, are known risk factors for thrombosis. The aim of the study was to evaluate the contribution of these mutations to thrombosis in Israeli patients with BD. Fifty-four patients with BD (n=54; 27 men and 27 women) underwent clinical and genetic evaluation. Most patients (n=43; 79.6%) were of Arab descent (31 sporadic and 12 familial cases from 4 families), and 11 patients (20.4%) were of Jewish descent (all sporadic cases). The FV Leiden mutation was identified in five patients (9.2%), and eight patients were MTHFR 677TT homozygotes (14.8%). None had the 20210A mutant prothrombin allele. No statistical differences between carriers and noncarriers with regards to demographic and disease manifestations were calculated. Arabs were diagnosed earlier than Jewish patients (25.8±11.6 compared with 37.2±10.7, p=0.01, respectively), but Jewish patients had, respectively, more events of deep vein thrombosis (DVT) compared with Arabs (3 of 11, 27.3% and 3 of 43, 7%, p=0.09). Thrombotic events in our patients with BD were not associated with variations in thrombophilic genes.

MEFV, TNFRSF1A and CARD15 mutation analysis in Behçet's disease.

OBJECTIVES: Given the pathological similarities between Behçet's disease (BD), Familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS) and Crohn's disease (CD) we evaluated the frequency of mutations and polymorphisms in MEFV, TNFRSF1A and CARD15 in Israeli BD patients of either Jewish or Arab descent. METHODS: Fifty-four BD patients (11 Jews and 43 Arabs), evaluated with respect to the entire spectrum of BD disease manifestations, were granted a systemic severity score for BD. An association between BD manifestations and MEFV, TNFRSF1A and CARD15 variants was analysed. RESULTS: Twelve patients (20.7%) displayed a single MEFV mutation and four patients (7.4%) had two mutated FMF alleles. Two patients (3.8%) carried a CARD15 variation and none carried a TNFRSF1A polymorphism. The frequency and distribution of mutated alleles between patients and controls was comparable (p=0.27). No statistically significant differences between carriers and non-carriers with respect to disease manifestations and severity score were calculated. Arab patients were diagnosed earlier than Jewish patients (25.8±11.6 and 37.2±10.7, respectively, p=0.06). CONCLUSIONS: The overall MEFV high carrier frequency in our cohort of BD patients seems to be attributed to their Mediterranean extraction rather than related to BD. The propensity of Arab patients (79.6%) in a cohort of BD patients from northern Israel is highlighted in face of their proportion (20%) in the general population lending further support to arguments that favour a genetic component for BD.