Nagwa A. Meguid

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Importance Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. Objectives To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Design, Setting, and Participants Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Results Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Conclusions and Relevance Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

Intellectual disability secondary to a 16p13 duplication in a 1;16 translocation. Extended phenotype in a four-generation family

We describe a large family from the Gaza Strip presented with multiple congenital anomalies. The proband was presented with intellectual disability and multiple congenital anomalies including cleft palate, low‐set ears, everted upper lip, diaphragmatic hernia, and arthrogryposis. Pedigree analysis showed 19 affected patients over five generations, only 6 were alive and 11 individuals were obligate carriers. The proband had an apparently normal karyotype, although FISH studies showed a derivative chromosome 1 with duplication of 16p13.3 and deletion of the 1p subtelomere. Her father however had a balanced translocation. The seven affected patients had a similar phenotype, one of them died before genetic testing was carried out and the living six patients had the same unbalanced translocation. Array CGH revealed an 8.8 Mb duplication in 16p13 and 200,338 bp deletion in 1p36.3. Accordingly, intellectual disability, hypertelorism, cupped ears, everted upper lip, and limb anomalies were presenting clinical features of the 16p13 duplication syndrome while deep set eyes were perhaps related to the 1p terminal deletion. Prevention of recurrent intellectual disability in this family can be achieved through carrier detection and prenatal genetic diagnosis.

Frequency of risk factors and coexisting abnormalities in a population of Egyptian children with autism spectrum disorder

BACKGROUND Many risk factors interact together during the critical period of development and govern the future phenotype of autism spectrum disorder (ASD). Furthermore, co-occurring abnormalities among individuals with ASD vary a lot so as their abilities. AIM OF WORK To investigate possible risk factors and to determine the prevalence of coexisting abnormalities in a sample of Egyptian ASD children and their influence on the severity and their communication performance. METHODS The diagnosis and severity of ASD for participants (N=80) was performed by DSM-5, ADIR and CARS. They were investigated regarding the possible risk factors and coexisting abnormalities. A detailed history taking, clinical examination, the Arabic preschool language scale, cognitive abilities assessment and other additional instrumental measures such as EEG were used. RESULTS Caesarian section and neonatal jaundice were the most common risk factors. The severity of ASD was positively related to maternal and paternal ages. Developmental language disorder, intellectual disability, attention deficit hyperactivity disorder, sleep disorder and EEG changes were more frequently detected among studied cases. The CARS scores were significantly higher in ADHD and EEG changes groups. The most severely affected CARS items in the groups with these disorders were determined. CONCLUSION High parental ages has an impact on the severity of ASD. ADHD, sleep disorder, and EEG changes seem to have an impact on certain elements of the adaptive behavior especially the communicative performance of ASD individuals. We recommend to seriously investigate co-morbid abnormalities and consider them during the process of management of ASD for proper intervention plans.

MRI Surface-Based Brain Morphometry in Egyptian Autistic and Typically Developing Children

Objectives: The verbal abilities of autistic children differ from those of typically developing ones and they also differ among autistic children themselves. Neuroanatomical changes and an abnormal organization of functional networks are expected to accompany such a neurodevelopmental disorder. The aim of this study was to delineate the brain neuroanatomical changes in Egyptian children with autism and to compare them with previous studies in order to add more insight into the global brain imaging deviations linked to autism. Patients and Methods: Twenty-five autistic children and 25 typically developing children underwent MRI. Further analysis was performed using surface-based morphometry to obtain cortical thickness, brain volume, and cortical complexity. Results: MRI analysis results revealed significantly greater cortical thickness, cortical complexity, and gray matter volume in the autistic as compared to the control group. On the other hand, the white matter volume was significantly smaller. Conclusion: These findings generally align with findings in previous studies, except for occasional differences.

Epilepsy and autistic manifestations in an Egyptian child with ring 14

BackgroundRing chromosomes are rare chromosomal disorders. Patients carrying a ring chromosome have different phenotypes depending on the degree of structural rearrangement. Subject and methodsWe observed an 8-year-old patient attending the clinic for autistic disorders. By cytogenetic analysis, we identified a de-novo ring chromosome 14. ResultsOur patient had a rare condition of developmental delay, behavioral hyperactivity, anxiety, and autistic traits in addition to severe drug-resistant epilepsy, indicating that these features might be part of a syndromic condition. In comparison with other ring 14 patients, the neurological features seen in this patient were extremely severe, in addition to having low-functioning autism. ConclusionWe believe that chromosome 14qter can have a role in the etiology of autism; therefore, cytogenetic analysis should be considered in autistic children.

Nonmosaic partial duplication 12p: clinical and cytogenetic findings and review of the literature 12p duplication

We report on a male patient with de-novo pure partial trisomy 12p syndrome besides Robertsonian translocation. The patient had characteristic dysmorphic features such as low-set ear, a high forehead, flat occiput, long philtrum, and nystagmus. He also suffers from intellectual disabilities, seizures, hypotonia, and developmental delay. He has normal anthropometric measurements, and normal height, weight, and skull circumference. A cytogenetic study using the G-banding technique showed 45,XY, add (12)(p12.3), t(13;14)(q10q10). Karyotyping of the parents was performed, which indicated a normal result for the father and 45, XX, t(13;14)(q10;q10) for the mother. The fluorescence in-situ hybridization technique was performed for the patient using whole-chromosome paint 12 and subs telomere 12p. It showed that the add segment on chromosome 12p was derived from chromosome 12 and that 12p subtelomere was inverted and duplicated. Thus, the karyotype is 45, XY, dup (12)(p ter-p12.3), t(13;14)(q10q10). Comparison of the clinical and the cytogenetic findings of our patient with previously reported dup (12p) in the literature was carried out for better characterization and understanding of the phenotypic and cytogenetic relationship.