Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expressio

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features

Impact of Childhood Epilepsy on the Family

Whole family is affected when an illness appears in the family or when there is an uncertainty regarding the health of a member. Symptoms, therapy, course of the disorder, constraint of the daily activities and long term effects of childhood chronic diseases deeply impact health and structure of the families. Diagnosis of a chronic disease in children presents as a significant psychological and psychosocial risk factor to the parents and other family members. Despite these known facts, psychosocial problems of parents of epileptic children are often ignored and not even questioned. These parents frequently have to leave their jobs or ask for their elderly relatives to look after their children. This situation could lead to major financial and social problems, weakening in intrafamilial communication and disruption in family harmony. Childhood epilepsy brings a great strain on family’s resources as other chronic diseases do and alter the life of significant others. According to biopsychosocial model, schemas in family relations influence the psychological process of the family members while the biopsychosocial process of the sick individual affect the functionality of the family. In other words, epilepsy affects not only the sick individual but also the family union. The family has to face many problems after definite diagnosis of epilepsy. Majority of the studies conducted on this issue mainly focused on the quality of life and family relations of the sick child, whereas only a few studies searched for possible burden and resulting problems of family members caused by epilepsy. Physicians in charge should not only focus on physical and mental health of the sick children but also on the problems of other members in the family bearing in mind psychosocial influences of the disorder on them. Additionally, preventive methods should be administered to protect the family from developing mental health problems. A multidiscipline training program aiming to provide social and psychiatric support would increase the awareness of the families about their coping system with the disease and thus revise their likely dysfunctional approaches

The Relationship between the Waist Circumference and Increased Carotid Intima Thickness in Obese Children

Background: This study aimed to evaluate the cardiometabolic risk factors in normotensive obese and hypertensive obese (HT-obese) children by comparison of anthropomorphic measurements, fat distribution, carotid artery intima-media thickness (CIMT), and inflammatory markers. Methods: Fifty-three obese patients 10-18 years of age with a BMI-for-age/gender >95th percentile and 20 age- and gender-matched healthy volunteers enrolled in the study. Obese patients were divided into two groups according to the presence of hypertension (HT), as follows: HT-obese subgroup (n = 30) and nonhypertensive obese (non-HT-obese) subgroup (n = 23). Results: Weight standard deviation score (SDS), BMI-SDS, waist circumference (WC) SDS, and the fat tissue z-score were significantly higher (p < 0.001 for all) in the obese patients than the control groups. Obese patients had higher 24-hour systolic blood pressure (SBP) SDS and leptin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 levels. Furthermore, CIMT and CIMT-SDS were significantly higher in them. HT-obese patients (n = 30) had significantly higher WC-SDS and lower serum leptin and adiponectin levels than those of non-HT-obese group (n = 23). Finally, an association between increased CIMT-SDS and WC-SDS (beta = 0.399, p = 0.002) and 24-hour SBP-SDS (beta = 0.272, p = 0.009) was shown. Conclusions: Association between increased WC and HT implies the importance of central obesity in atherosclerosis. We concluded that WC measurement could be used to define risk groups since it is related to cardiometabolic complications