Variants in CUL4B are Associated with Cerebral Malformations

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B

Differential response of domestic and wild Lycopersicon species to chilling under low light: Growth, carbohydrate content, photosynthesis and the xanthophyll cycle

The response of five Lycopersicon species to 14 days moderate chilling at 10 degrees C under low light (75 mu mol m(-2) s(-1)) and subsequent recovery was examined by measurements on relative shoot growth rate, leaf dry matter and carbohydrate content, CO2-exchange and pigment composition. In addition, the susceptibility to dark chilling and temperature dependence of chloroplast electron transport were analyzed by Chl a fluorescence measurements. During 7 days of recovery at 25/20 degrees C subsequent to chilling, the domestic tomato Lycopersicon esculentum (L.) Mill. cv. Abunda exhibited a small capacity for shoot regrowth (39%) compared to the low-altitude wild species L. pimpinellifolium (Jusl.) Mill. PI187002 (82%) and three wild species originating from high altitude: L, peruvianum Mill. LA 385 (92%), L, hirsutum Humb, & Bonpl. LA 1777 (67%) and L. chilense Dunn. LA 1970 (71%). The inter-specific differences in chilling sensitivity at the chloroplast level, analyzed by the decline of the maximum rate of induced Chl fluorescence rise (F-R) after 40 h at 0 degrees C and the temperature at which q(P) reached the value 0.5, correlated in general well with the measured differences at whole plant level, measured by the post-chilling regrowth capacity. Chilling resulted in a larger increase in leaf dry matter content in L. esculentum (45%) and L. pimpinellifolium (37%) compared to the high-altitude species (13-16%), which could be attributed to a stronger accumulation of both soluble sugars and starch in mature leaves of the domestic and low-altitude species. Photosynthetic and dark respiration rates during chilling could not account for this difference, The recovery of photosynthesis was better in the high-altitude species, Chl content per unit leaf area decreased more throughout the experiment in the domestic and low-altitude species (63-73%) than in their relatives from high altitude (8-29%), In response to chilling, the domestic and low-altitude species showed an increase in the total xanthophyll cycle pool on Chl basis, whereas the de-epoxidation state of the xanthophyll cycle increased in the high-altitude wild species. Both responses resulted in increased zeaxanthin levels in chilled leaves of all Lycopersicon species

Dilemma of Reporting Incidental Findings in Newborn Screening Programs for SCID: Parents' Perspective on Ataxia Telangiectasia.

Background: Ataxia Telangiectasia (A-T) is a severe DNA repair disorder that leads to a broad range of symptoms including neurodegeneration and a variable immunodeficiency. A-T is one of the incidental findings that accompanies newborn screening (NBS) for severe combined immunodeficiency (SCID), leading to an early diagnosis of A-T at birth in a pre-symptomatic stage. While some countries embrace all incidental findings, the current policy in the Netherlands on reporting untreatable incidental findings is more conservative. We present parents' perspectives and considerations on the various advantages vs. disadvantages of early and late diagnosis of A-T. Methods: A questionnaire was developed and sent to 4,000 parents of healthy newborns who participated in the Dutch SONNET-study (implementation pilot for newborn screening for SCID). The questionnaire consisted of open-ended and scale questions on advantages and disadvantages of early and late diagnosis of A-T. To address potential bias, demographic characteristics of the study sample were compared to a reference population. Results: A total of 664 of 4,000 parents sent back the questionnaire (response rate 16.6%). The vast majority of parents (81.9%) favored early diagnosis of A-T over late diagnosis. Main arguments were to avoid a long period of uncertainty prior to diagnosis and to ensure the most optimal clinical care and guidance from the onset of symptoms. Parents who favored late diagnosis of A-T stated that early diagnosis would not lead to improved quality of life and preferred to enjoy the asymptomatic "golden years" with their child. The majority of parents (81.1%) stated that they would participate in newborn screening for A-T if a test was available. Conclusions: Reporting untreatable incidental findings remains a disputed topic worldwide. Although the current policy in the Netherlands is not to report untreatable incidental findings, unless the health advantage is clear, the majority of parents of healthy newborns are in favor of an early A-T diagnosis in the pre-symptomatic phase of the disorder. Our results as well as other studies that showed support for the screening of untreatable disorders may serve as valuable tools to inform policymakers in their considerations about NBS for untreatable disorders

A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients

Introduction: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients. Methods: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5–46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity. Results: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex. Conclusion: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains to be further elucidated

Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome

Item does not contain fulltextWe studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype

De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Purpose To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. Methods We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. Results All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. Conclusions The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.6 month embargo; published online: 28 November 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Homozygosity mapping in outbred families with mental retardation

Autosomal recessive mental retardation (AR-MR) may account for up to 25% of genetic mental retardation (MR). So far, mapping of AR-MR genes in consanguineous families has resulted in six nonsyndromic genes, whereas more than 2000 genes might contribute to AR-MR. We propose to use outbred families with multiple affected siblings for AR-MR gene identification. Homozygosity mapping in ten outbred families with affected brother–sister pairs using a 250 K single nucleotide polymorphism array revealed on average 57 homozygous regions over 1 Mb in size per affected individual (range 20–74). Of these, 21 homozygous regions were shared between siblings on average (range 8–36). None of the shared regions of homozygosity (SROHs) overlapped with the nonsyndromic genes. A total of 13 SROHs had an overlap with previously reported loci for AR-MR, namely with MRT8, MRT9, MRT10 and MRT11. Among these was the longest observed SROH of 11.0 Mb in family ARMR1 on chromosome 19q13, which had 2.9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes

Mutations in MED12 Cause X-Linked Ohdo Syndrome

<p>Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.</p>

Variants in CUL4B are Associated with Cerebral Malformations

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Mutations in DDHD2, Encoding an Intracellular Phospholipase A(1), Cause a Recessive Form of Complex Hereditary Spastic Paraplegia

Contains fulltext : 108770.pdf (publisher's version ) (Closed access)We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease