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Background: Intellectual disability (ID), or developmental delay (DD) when the individual is yet under 5 years of age, is evident before 18 years of age and is characterised by significant limitations in both intellectual functioning and adaptive behaviour. ID/DD may be clinically classified as syndromic or non‐syndromic. Genomic copy number variations (CNVs) constitute a well‐established aetiological subgroup of ID/DD. Overall diagnostic yield of microarrays is estimated at 10–25% for ID/DD, especially higher when particular clinical features that render the condition syndromic accompany. Methods: In this study, we aimed to investigate the diagnostic yield of microarrays in the subgroup of individuals with non‐syndromic ID/DD (NSID/NSDD). A total of 302 NSID/NSDD individuals who have undergone microarray analysis between October 2013 and April 2020 were included. Accompanying clinical data, including head circumference, delayed developmental areas, seizures and behavioural problems were collected and analysed separately in NSID and NSDD subgroups. Results: The diagnostic yield of microarray analyses in NSID/NSDD was determined as 10.9% in NSID (10.7%) and in NSDD (11.1%). Presence of behavioural and epileptic problems did not contribute to the diagnostic yield. However, in the presence of macrocephaly, the contribution to diagnostic yield was statistically significant particularly in NSDD group. The most common pathogenic CNVs involved chromosomes 16, 15 and X. Lastly, we propose a Xq21.32q22.1 deletion as likely pathogenic in a child with isolated language delay and accompanying seizures. Conclusions: Particularly in neurodevelopmental diseases, microarrays are useful for establishing the diagnosis and detecting novel susceptibility regions. Future studies would accurately classify the herein presented variants of uncertain significance CNVs as pathogenic or benign. [ABSTRACT FROM AUTHOR]

Background: Aetiological diagnosis in non‐syndromic intellectual disability (NSID) still poses a diagnostic challenge to clinicians. Methods: Screening is currently achieved by chromosomal microarrays followed by whole‐exome sequencing (WES). In search for the aetiological yield of WES in patients with NSID, 59 unrelated patients were studied. Results: Among the 59 patients, 44 (74.6%) were from consanguineous unions. Epilepsy was present in 11 (37.9%), behavioural problems in 12 (41.4%) and autistic features in 14 (48.3%). WES analysis resulted in molecular diagnosis in 29 patients (49.2%). Some of the genes were specific for nervous system functioning, like HERC1, TBC1D7, LINS, HECW2, DEAF1, HNMT, DLG3, NRXN1 and HUWE1. Others were ubiquitously expressed genes involved in fundamental cellular processes, like IARS, UBE3A, COQ4, TAF1, SETBP1, ARV1, ZC4H2, KAT6A, ASXL3, THOC6, HNRNPH2, TUBA8 and KIF1A. Twenty‐two (75.8%) were consanguineously married; however, only 12 (41.4%) of the detected genes caused autosomal recessive phenotypes. Conclusions: This cohort suggests that recessive genes probably represent an actually smaller subgroup of NSID, even among families with consanguinity. Although in societies with high consanguinity rates, considering the recessive inheritance first seems to be an advantageous strategy, de novo mutations in autosomal dominantly expressed genes represent the major aetiological group in patients with NSID, even among those patients from consanguineous families. [ABSTRACT FROM AUTHOR]

Background: Rearrangement of the 1q21 region of chromosome 1 manifests as multiple phenotypes, including microcephaly, intellectual disability, dysmorphic facial features, eye abnormalities, cardiac defects, genitourinary anomalies, autism spectrum disorder, psychiatric conditions and seizures. Herein, we describe eight patients with 1q21 deletion and duplication syndromes, and novel deletions and findings. Methods: Chromosomal microarray analysis was performed to identify the existence of copy number variation. Quantitative polymerase chain reaction was applied using specific primers for the control and 1q21 region of chromosome 1. Mutational analysis was performed in case 5 using direct genomic sequencing for exons 1–6 in RBM8A. Results: Copy number variation analysis identified seven deletions and one duplication of the 1q21 region in the eight patients. In addition, four variations were de novo, and two deletions are reported here for the first time. One of the cases (case 7) presents moderate intellectual disability and dysmorphic facial findings, whereas chromosomal microarray analysis showed that case 7 had an 889‐kb deletion in the 1q21 proximal region (GPR89A, PDZK1, CD160, POLR3C and NBPF12). Conclusion: Although the deletion in case 5 did not include the thrombocytopenia‐absent radius syndrome critical region or the RBM8A gene, he had pectoral muscle hypoplasia, radius and humerus hypoplasia and short curved ribs, which are indicative of a potential thrombocytopenia‐absent radius region modifier. The findings in case 7 suggest that the proximal part of the 1q21 microdeletion syndrome region might be very important for the onset of clinical manifestations. Some novel findings were observed in the presented cases, such as radius and humerus hypoplasia and brain stem hypoplasia. The presented findings expand the spectrum of 1q21 aberrations and provide evidence of genotype–phenotype correlations for this region. [ABSTRACT FROM AUTHOR]

HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1 . Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations. [ABSTRACT FROM AUTHOR]

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition. [ABSTRACT FROM AUTHOR]

GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. GRID2 encodes the glutamate receptor subunit delta-2, selectively expressed in cerebellar Purkinje cells. The phenotype associated with loss of GRID2 function was described only in mice until now, characterized by different degrees of cerebellar ataxia and usually relatively mild abnormalities of the cerebellum. This work describes for the first time the human phenotype associated with homozygous partial deletion of GRID2 in 3 children in one large consanguineous Turkish family. Homozygous deletion of exons 3 and 4 of GRID2 (94 153 589-94 298 037 bp) in the proband and similarly affected cousins, and heterozygous deletions in parental DNA were shown using Affymetrix® 6.0 single-nucleotide polymorphism array, confirmed by real-time polymerase chain reaction. The phenotype includes nystagmus, hypotonia with marked developmental delay in gross motor skills in early infancy followed by a static encephalopathy course with development of cerebellar ataxia, oculomotor apraxia, and pyramidal tract involvement. [ABSTRACT FROM PUBLISHER]

Introduction/Background There are no studies evaluating compatibility of visual gait assessment scales and Gait Deviation Index (GDI), Gait Variability Index (GVI) in individuals after stroke. The study was designed to compare results of the observational Wisconsin Gait Scale (WGS) and the global gait indexes such as GDI and GVI, constituting an objective method of assessing gait. The objective was to answer the question whether simple, inexpensive, easy to use, observational WGS may be an effective alternative for costly equipment-based analyses in assessing gait after stroke. Material and method The study group comprised 50 participants who had experienced a stroke and were in a chronic phase of recovery, as well as 50 healthy individuals, without gait disorders. The subjects’ gait was evaluated using the WGS, and the GDI and GVI values were acquired using a 3-dimensional gait analysis system. GDI was calculated based on kinematic parameters, while GVI was computed from spatiotemporal parameters. Results The study has shown statistically significant correlations between the parameters of GDI affected leg and WGS total score (R = −0.87), GVI affected leg and WGS total score (R = −0.93), GVI unaffected leg and WGS total score (R = −0.88), GVI affected/unaffected leg and the total score in the assessment of spatiotemporal parameters on the WGS (R = −0.81) as well as GDI affected leg and the total score in the assessment of kinematics parameters on the WGS (R = −0.85). All correlations were strong (0.7 ≤ |R| < 0.9) or very strong (0.9 ≤ |R| < 1). Conclusion There is a strong or very strong correlation of the GDI and GVI to the WGS scores. WGS is an excellent tool enabling qualitative assessment of gait abnormalities in individuals after a stroke, and providing results, which correspond with the objective assessment of spatiotemporal and kinematic gait parameters, i.e. by means of global gait indexes. WGS should be applied in daily clinical practice. [ABSTRACT FROM AUTHOR]