Clinical and genetic characterization of intellectual disability.

Intellectual disability affects 1% to 3% of the global population, occurs more frequently in males than females, and has higher prevalence in low- and middle-income countries than in high-income countries.1 The intellectual disability spectrum varies widely from mild to severe, and may be non-syndromic, or associated with additional neurological features or additional organ system involvement such as congenital anomalies, hearing or visual impairment, or epilepsy. Identifiable causes of intellectual disability may be environmental (infectious, teratogenic, intraventricular hemorrhage associated with preterm birth, etc.) or genetic (chromosomal aneuploidy, copy number variants or structural anomalies, monogenic X-linked, recessive, or de novo autosomal conditions, mitochondrial or imprinted disorders). The genetic diagnostic tools available to clinicians have evolved over the past two decades from fragile X and karyotyping to next-generation sequencing allowing for testing panels of hundreds of genes, up to exome or genome sequencing. Recently, exome or genome sequencing have come into the mainstream as first-line genetic testing for most children with developmental delay/intellectual disability or multiple congenital anomalies.2, 3 Venetvaara et al.4 report a population-based retrospective study of a cohort of 959 children with intellectual disability seen between 2017 and 2021 at an academic hospital in Finland. Since the genetic testing occurred over a 22-year period, a wide range of standard genetic testing was performed with chromosomal microarray, fragile X, exome sequencing, and karyotype being the most common with an overall diagnostic yield of 437 out of 959 (46%) patients. In this real-world study, the most important insights came from clinical characterization by confirmation through records review of: the diagnosis and severity of intellectual disability, assessment for additional significant clinical features, and assessment for preterm birth and environmental causes of intellectual disability. The authors' detailed review showed that chromosomal anomalies were enriched in patients with intellectual disability and congenital heart disease, and monogenic variants were more common in patients with intellectual disability and epilepsy or ophthalmological abnormalities. Furthermore, associated conditions resulting in congenital heart disease, visual impairment, hearing impairment, autism spectrum disorder, or epilepsy were more common with more severe intellectual disability. This suggests that patients with moderate or severe intellectual disability may need screening for certain medical conditions at the time of diagnosis, and in some cases, further evaluation for comorbidities during follow-up. Other important lessons from the present study for clinical practice were that 90 out of 959 (9%) patients had non-genetic causes of intellectual disability, most related to preterm birth or hemorrhage, and that 18 out of 165 (11%) individuals were diagnosed with a potentially treatable genetic metabolic conditions. Not all insights gained from this study are likely to apply to other populations. For example, in this cohort consisting of almost entirely patients of Finnish ancestry, there was a substantial number of patients with autosomal recessive metabolic diseases with likely pathogenic/pathogenic founder variants enriched in persons of Finnish heritage. The ability to identify a cause of intellectual disability for almost half of children with current technology is remarkable progress. Understanding of the causes for the remaining half is an area of active investigation and future research, with the promise of additional discoveries through long-read sequencing, methylation studies, genome sequencing, RNA sequencing and transcriptomics, metabolomics, and the integration of multi-omic data.5 Not required.

X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family. Consanguineous Eastern European-Australian family Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous. Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans.

Objective To analyze the clinical and molecular genetic characterizations of X-linked adrenal dysplasia congenita(AHC) onset in infant. Methods Seven children (from 7 families) with X-linked AHC who were admitted to the Department of Endocrinology, Genetics and Metabolism, Children′s Hospital Affiliated to Zhengzhou University, from July 2012 to June 2017 were selected.All patients were screened for dosage-sensitive-sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene1 (DAX1/NR0B1) mutations.The clinical manifestation and laboratory examination were analyzed, their clinical characterizations were summarized. Results Seven patients were all male, the onset age of the patients were from after birth to 7 months old, and 4 patients (4 families) had a family history of X-linked recessive inheritance.The clinical manifestations were skin pigmentation[100.0%(7/7 cases)], vomiting [71.4%(5/7 cases)], no weight gain [57.1%(4/7 cases)]and poor spirit [28.6%(2/7 cases)]. Laboratory tests showed that hyperkalemia and hyponatremia, increased coricotrophin, normal or decreased cortisol, 17α-hydroxyprogesterone, progesterone, aldosterone and dehydroepiandrosterone.Testosterone levels increased in 5 patients.The abnormalities of adrenal glands imaging could be seen in 2 patients.Two patients were misdiagnosed as congenital adrenal cortical hyperplasia.Then the definitive diagnosis were made by genetic test.DAX1/NR0B1 gene mutations were found in all patients.Five patients were novel mutations (c.114_126del, c.872G>A, c.56delG, c.884T>G, c.1217delG). Conclusions The clinical manifestations of X-linked AHC with infant onset include pigmentation, poor spirit and growth retardation, which should be differentiated from congenital adrenal cortical hyperplasia.Hormone levels such as elevated blood 17α-hydroxyprogesterone and family history are the main identification points, and AHC cannot be excluded when testosterone level increases.Five novel mutations are found in this study, which enrich the gene database. Key words: Adrenal hypoplasia congenita; Dosage-sensitive-sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene 1; Gene mutation; Adrenal insufficiency

The p.E22G mutation in the Cu/Zn superoxide-dismutase gene predicts a long survival time : Clinical and genetic characterization of a seven-generation ALS1 Spanish pedigree

BackgroundIncreased incidence of papillary thyroid carcinoma (PTC) is observed as a consequence of radiation exposure in connection to the Chornobyl nuclear plant accident in 1986. In this study, we report a cohort of adult Ukrainian patients diagnosed with PTC from 2004 to 2008 following exposure at the age of 18 years or younger.MethodsIn total, 70 patients were identified and clinically characterized. The common BRAF 1799T>A mutation was assessed by pyrosequencing, the RET/PTC1 and RET/PTC3 (NCOA4) rearrangements by RT-PCR, and the expression of Ki-67 (MIB-1 index), BCL2, cyclin A, and cyclin D1 by immunohistochemistry.ResultsIn total, 46/70 (66%) cases carried a BRAF mutation and/or a RET/PTC rearrangement. A BRAF mutation was detected in 26 tumors, RET/PTC1 in 20 cases, and RET/PTC3 in four cases. In four of these cases, BRAF mutation and RET/PTC rearrangement were coexisting. The BRAF mutation was underrepresented among PTCs with accompanying chronic lymphocytic thyroiditis (CLT) compared with PTCs without this feature (12 vs 44%). MIB-1 proliferation index determined by double staining with leukocyte common antigen was low (mean 0.8%; range 0.05–4.5%). Moreover, increased expression of cyclin A was observed in PTCs with a tumor size >2 cm compared with PTCs ≤2 cm (1.2 vs 0.6%). BCL2 and cyclin D1 showed frequent expression but without associations to clinical characteristics or amplification of the CCND1 locus.ConclusionsOur results suggest that this cohort has frequent BRAF mutation, RET/PTC1 rearrangement, and low proliferation index. Furthermore, BRAF 1799T>A was underrepresented in PTCs with CLT, and cyclin A expression was associated with increased PTC tumor size.

Mutations in the gap junction protein beta 1 gene (GJB1) cause X-linked Charcot-Marie-Tooth disease type 1 (CMTX1). CMTX1 is representative of the intermediate type of CMT, having both demyelinating and axonal neuropathic features. We analyzed the clinical and genetic characterization of 128 patients with CMTX1 from 63 unrelated families. Genetic analysis revealed a total of 43 mutations including 6 novel mutations. Ten mutations were found from two or more unrelated families. p.V95M was most frequently observed. The frequency of CMTX1 was 9.6% of total Korean CMT family and was 14.8% when calculated within genetically identified cases. Among 67 male and 61 female patients, 22 females were asymptomatic. A high-arched foot, ataxia, and tremor were observed in 87%, 41%, and 35% of the patients, respectively. In the male patients, functional disability scale, CMT neuropathy score, and compound muscle action potential of the median/ulnar nerves were more severely affected than in the female patients. This study provides a comprehensive summary of the clinical features and spectrum of GJB1 gene mutations in Korean CMTX1 patients.

Genetic disorders affecting the arterial tree in the form of aneurysms and dissections are highly morbid conditions that strike younger persons leading to bleeding, infarction, or even death. Although clinically recognizable syndromes, notably Marfan, Ehlers Danlos, and Loeys-Dietz syndromes encompass the principal diagnosable phenotypes along the genetic vascular disorder spectrum, a substantial subset of patients cannot be adequately classified under a known diagnosis through clinical or molecular diagnostic methods. Here we describe patients presenting with multiple-aneurysms and/or pseudoaneurysm syndromes (MAPS), and clinically characterize this novel phenotype, present data on natural history and prognosis, and propose management guidelines. Thirty-two patients with MAPS were identified from February 2006 to October 2015 through the University of Colorado Adult Medical Genetics Clinic. A subset of patients underwent clinical genetic testing utilizing the Marfan/TAAD/Related disorders panel, and another subset was enrolled for research-based exome-sequencing. Thirty-two patients (10 men, 22 women) were classified as MAPS patients with an average age of diagnosis at 39.5 (±13.3) and 35.4 (±12.8) years, respectively. Symptom presentation and progression are presented based on vascular territory, notably of the heart, head, and neck, which could manifest with fatal complications. Secondary arterial events occurred at an average of 6.7±6.0 years after the initial MAPS episode. Genetic analysis revealed 9 gene variants that are likely pathogenic and implicated in MAPS. These data more broadly illuminate a phenotype of aneurysms, dissections, and/or pseudoaneurysms that do not classify under a recognizable genetic vascular diagnosis. Our data should provide useful clinical information for providers managing patients with MAPS.

Clinical features and genetic characterization of two dizygotic twins with C9orf72 expansion.

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Nagashima-type palmoplantar keratosis (NPPK) is the most prevalent palmoplantar keratoderma (PPK) in East Asia. Homozygous or compound heterozygous loss-of-function mutations in serpin peptidase inhibitor, clade B (ovalbumin), and member 70 (SERPINB7), which encodes members of the serine protease inhibitor superfamily, have been identified as the cause of NPPK. Clinical manifestations of NPPK include well-demarcated erythema, mild to moderate hyperkeratosis on the whole palm, and sole with transgrediens, extending to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon areas. In this study, we perform a review of relevant clinical cases aimed at elucidating the clinical characteristics, genetic characterization, differential diagnoses, and clinical management of NPPK. A better understanding of the clinical characteristics and pathogenic gene characterization of NPPK will enhance the diagnosis of NPPK, identify related diseases, and inform on the precise therapy and prognosis. Moreover, it will promote the awareness of NPPK in non-Asian regions.

Genetic and Clinical Characterization of 45 Acute Leukemia Patients with MLL Gene Rearrangements From a Single Institution.

Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome

The KCNB1 gene encodes a voltage-dependent potassium channel that regulates transmembrane currents in pyramidal neurons. Heterozygous variants have recently been associated with early-onset epileptic encephalopathies and intellectual disability, but their clinical characterisation has not yet been fully defined. To describe the clinical spectrum associated with variants of KCNB1 in paediatric patients. Retrospective study of four patients from three families with KCNB1 encephalopathy, including an analysis of the clinical and electroencephalographic features of epilepsy, associated neurological manifestations and neurodevelopmental pattern. In two of them, the mutation in KCNB1 was de novo; the other two, who were sisters, inherited the variant from a parent with germline mosaicism. All had mild-to-moderate intellectual disability, two patients had autistic spectrum disorder and two had attention deficit hyperactivity disorder. Only case 2 displayed alterations in the MRI brain scan: progressive cortical atrophy. Three of them developed epilepsy (cases 1-3). Case 1: onset at 9.5 months with West syndrome that was well controlled with vigabatrine and zonisamide. Case 2: onset at 13 months with West syndrome, evolutionary development of polymorphic seizures (atonic, hypermotor, dysautonomic and tonic) that were refractory to 10 antiepileptic drugs and corticosteroids. Accompanied by a movement disorder characterised by ataxia, dyskinesias and tremor. Case 3: onset at 14.5 years with atonic seizures, multifocal EEG pattern and adequate control with levetiracetam. KCNB1 encephalopathy has a heterogeneous natural history, mainly with respect to epilepsy, ranging from patients with refractory epilepsy to patients without any epileptic seizures. All had neurodevelopmental disorders, such as intellectual disability or autism spectrum disorder, independent of epilepsy.

To examine the clinical and genetic characteristics of intellectual disability. We conducted a population-based retrospective analysis on the clinical and genetic data of 959 children with diagnosed intellectual disability during a 5-year period (2017-2021) at Oulu University Hospital, Finland. Pathogenic or likely pathogenic gene variants were detected in 89 of 194 patients (46%) who underwent exome sequencing. Chromosomal abnormalities, including those with low penetrance, were observed in 106 of 530 patients (20%) who underwent chromosomal microarray testing. Chromosomal abnormalities and causative gene variants were more frequently identified in patients with moderate to profound intellectual disability than in those with mild intellectual disability; however, this difference was not significant in the diagnostic yield analysis. Epilepsy, congenital heart disease, hearing loss, ophthalmological abnormalities, and autism spectrum disorder were more common among patients with moderate to profound intellectual disability, whereas attention-deficit/hyperactivity disorder was associated with mild intellectual disability. Chromosomal abnormalities were associated with congenital heart disease and hearing loss, while pathogenic gene variants were associated with epilepsy and ophthalmological abnormalities. Somatic comorbidities were more common in moderate to profound intellectual disability, whereas attention-deficit/hyperactivity disorder was more frequent in mild intellectual disability.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have been described in only six individuals carrying five biallelic predicted loss-of-function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including 15 new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were observed uniformly, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches might ameliorate some symptoms caused by RBL2 pLOF.