Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders.

While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology of neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable of capturing SVs that are undetectable or challenging-to-detect via short-read methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases that remained unsolved after standard exome sequencing. OGM was performed in 47 families using ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV and copy number variant calling. We identified 7 variants of interest, of which 5 (10.6%) were classified as likely pathogenic or pathogenic, located in BCL11A, OPHN1, PHF8, SON, and NFIA. We also identified an inversion disrupting NAALADL2, a gene which previously was found to harbor complex rearrangements in two NDD cases. Variants in known NDD genes or candidate variants of interest missed by exome sequencing mainly consisted of larger insertions (> 1kbp), inversions, and deletions/duplications of a low number of exons (1-4 exons). In conclusion, in addition to improving molecular diagnosis in NDDs, this technique may also reveal novel NDD genes which may harbor complex SVs often missed by standard sequencing techniques.

A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.

Bilateral perisylvian polymicrogyria (BPP) is a structural malformation of the cerebral cortex that can be caused by several genetic abnormalities. The most common clinical manifestations of BPP include intellectual disability and epilepsy. Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a protein that interacts with the fragile X mental retardation protein (FMRP). CYFIP2 variants can cause various brain structural abnormalities with the most common clinical manifestations of intellectual disability, epileptic encephalopathy and dysmorphic features. We present a girl with multiple disabilities and BPP caused by a heterozygous, novel, likely pathogenic variant (c.1651G>C: p.(Val551Leu) in the CYFIP2 gene. Our case report broadens the spectrum of genetic diversity associated with BPP by incorporating CYFIP2.

Manifestations of Intellectual Disability, Dystonia, and Parkinson's Disease in an Adult Patient with ARX Gene Mutation c.558_560dup p.(Pro187dup).

We describe a 38-year-old male patient with intellectual disability and progressive motor symptoms who lacked an etiological diagnosis for many years. Finally, clinical exome sequencing showed a likely pathogenic variant of the ARX gene suggesting Partington syndrome. His main symptoms were mild intellectual disability, severe kinetic apraxia, resting and action tremor, dysarthria, tonic pupils, constant dystonia of one upper limb, and focal dystonia in different parts of the body, axial rigidity, spasticity, epilepsy, and poor sleep. Another likely pathogenic gene variant was observed in the PKP2 gene and is in accordance with the observed early cardiomyopathy. Single-photon emission computed tomography imaging of dopamine transporters showed a reduced signal in the basal ganglia consistent with Parkinson's disease. Therapies with a variable number of drugs, including antiparkinsonian medications, have yielded poor responses. Our case report extends the picture of the adult phenotype of Partington syndrome.

Report of a novel missense mutation in the MECP2 gene in a middle-aged man with intellectual disability syndrome.

Exome sequencing revealed the cause of our 35-year-old male patient's progressive and severe intellectual and motor disability, namely a previously undescribed missense mutation of MECP2.

Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation.

BACKGROUND: Phelan-McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. METHOD: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings' and the parents' DNA sample. RESULTS: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. CONCLUSION: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.

Natural history of alpha-thalassemia X-linked intellectual disability syndrome: A case report of a 45-year-old man.

We have followed the clinical course of a 45-year-old man with a severe form of alpha-thalassemia X-linked intellectual disability syndrome for 40 years. The most challenging health issue is the combination of rumination, drooling, and vomiting. The patient achieved present adaptive and motor skills in his teenage years. He is able to move on the floor in a sitting position. He seems happy and has not shown any behavioral or psychiatric symptoms. New signs not described in the literature before are accelerated growth after puberty and atypical sleeping position with upper body resting on legs.

Screening of dementia indicating signs in adults with intellectual disabilities.

BACKGROUND: In intellectual disability, the cognitive delay is observed during developmental age, whereas in dementia, cognitive decline occurs during post-developmental period. So far, the risk of dementia in people with intellectual disability, excluding those with Down syndrome, is poorly known. METHOD: We screened dementia signs in a study group of 230 adults (34-80 years of age) with the help of the British Present Psychiatric State-Learning Disabilities assessment. RESULTS: Of the study members, 42% showed two or more signs. The overall frequency of symptoms did not differ between age groups. The number of individuals with a genetic syndrome or disease manifesting with a shortened lifespan was greater in the younger age groups when compared to the older age groups. CONCLUSION: People with an intellectual disability represent numerous rare syndromes with comorbidities. It seems that dementia signs may affect any age groups of adults with intellectual disability.

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

Adult phenotype of the homozygous missense mutation c.655G>A, p.Gly219Arg in SLC13A5: A case report.

Homozygous recessive or compound heterozygous mutations in SLC13A5-gene as a cause of Early Infantile Epileptic Encephalopathy subtype 25 (OMIM 615905) were published in 2014. Previous clinical reports describe young patients, aged <34 years. We describe 54- and 56-year-old siblings and show that the disorder linked to SLC13A5 is not just a pediatric problem but may affect the patient for decades resulting in profound intellectual disability, severe motor handicap, and abnormal electroencephalography without active epilepsy. Other diagnostic hints in adults are small size, spasticity and severe abrasion due to amelogenesis imperfecta of the hypoplastic type.

Two novel intragenic variants in the FMR1 gene in patients with suspect clinical diagnosis of Fragile X syndrome and no CGG repeat expansion.

The major and most well-studied genetic cause of Fragile-X syndrome (FXS) is expansion of a CGG repeat in the 5'-UTR of the FMR1 gene. Routine testing for this expansion is performed globally. Overall, there is a paucity of intragenic variants explaining FXS, a fact which is being addressed by a more systematic application of whole exome (WES) and whole genome (WGS) sequencing, even in the diagnostic setting. Here we report two families comprising probands with a clinical suspicion of FXS and no CGG repeat expansions. Using WES/WGS we identified deleterious variants within the coding region of FMR1 in both families. In a family from Finland we identified a complex indel c.1021-1028delinsTATTGG in exon 11 of FMR1 which gives rise to a frameshift and a premature termination codon (PTC), p.Asn341Tyrfs*7. Follow-up mRNA and protein studies on a cell line from the proband revealed that although the mRNA levels of FMR1 were not altered, Fragile X Mental Retardation 1 Protein (FMRP) was undetectable. Additionally, we identified a variant, c.881-1G > T, affecting the canonical acceptor splice site of exon 10 of FMR1 in an Australian family. Our findings reinforce the importance of intragenic FMR1 variant testing, particularly in cases with clinical features of FXS and no CGG repeat expansions identified.

Ageing and cognition in men with fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. The aim of our longitudinal study was to describe ageing-related cognitive changes in men with FXS. METHOD: A neuropsychologist determined the raw scores (RSs) of 19 men with FXS twice with the Leiter International Performance Scale at an average interval of 22 years. The ages of the participants at baseline ranged from 16 to 50 (mean 27) years. RESULTS: At follow-up, the RSs improved in two men, remained the same in two men and declined in 15 men. Overall, the RS of the study group deteriorated by an average 4 points in RSs (p < .001). CONCLUSION: Cognitive ageing in men with FXS started earlier than that in men in the general population; in many cases, cognitive ageing in men with FXS began before middle age, usually without any medical or other underlying cause.

Two middle-aged women with the Finnish variant of muscle-eye-brain disease (MEB).

Muscle-eye-brain disease (MEB) is a recessively inherited rare disease. Sixteen different gene mutations are known, with the most common mutations in the POMGNT1 gene. The disease is now called congenital muscular dystrophy-dystroglycanopathy type A3 (MDDGA3). It manifests itself as muscular dystrophy with eye and brain anomalies and intellectual disability. Previous clinical reports describe young patients. We have been able to follow two patients for almost 40 years. Their clinical picture has remained quite stable since adolescence, appearing as severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, joint contractures, repeated bowel obstructions, teeth abrasion due to bruxism, an irregular sleep pattern and as a previously unreported feature hypothermic periods manifesting as excessive sleepiness.

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females.

Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9-edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.

Cognition in adults with Williams syndrome-A 20-year follow-up study.

BACKGROUND: Williams syndrome (WBS) is a genetic multisystem disorder. The main symptom is borderline (intelligence quotient, IQ 70-79) or abnormally low intelligence (IQ < 70). According to earlier studies young individuals with WBS demonstrate generally a slightly higher verbal IQ (VIQ) compared to performance/nonverbal IQ (PIQ). WBS was recognized as a distinct entity already about 60 years ago, but still cognition in adults with WBS is poorly known. METHODS: We followed 25 adults (age at baseline 19-68, median 38) with genetically confirmed WBS for about 20 years. The study subjects underwent medical and neuropsychological assessments at the baseline and at the end of follow-up. RESULTS: The mean VIQ remained quite stable from early adulthood up to 40 years of age after which it declined. The mean PIQ kept on improving from early adulthood until 50 years of age after which it gradually declined. At the end of the study, all study subjects had at least two longstanding health problems out of which hypertension, psychiatric disorder, and scoliosis or kyphosis occurred most frequently. At end of the study, two patients suffered from vascular dementia. Seven patients died during the follow-up. CONCLUSIONS: In adults with WBS, the course of cognition is uneven across the cognitive profile. Their verbal functions both develop and deteriorate earlier than performance/nonverbal functions. Frequent somatic co-morbidities may increase risk to shortened life span.

Signs indicating dementia in Down, Williams and Fragile X syndromes.

BACKGROUND: Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups. METHODS: Using the British Present Psychiatric State-learning Disabilities assessment (PPS-LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. The median age of those with FXS (59 years) was higher than of those with DS (50 years) and WS (53 years). RESULTS: Most study participants with DS (80%) and FXS (89%) were or had been moderately or severely intellectually disabled while most participants with WS (73%) were or had been mildly or moderately disabled at adolescent age. The adolescent (premorbid) level of ID did not correlate with the dementia score. The median scores were 11/27, 1/27, and 0/27 in DS, WS, and FXS subgroups, respectively. Dementia that was confirmed by brain imaging, manifested as Alzheimer disease and as moya-moya disease associated vascular dementia in DS and as vascular dementia in WS. CONCLUSIONS: This survey suggests that the risk of dementia varies depending on the cause of ID and that the severity of ID in adolescence does not predict the development of dementia at a later age. Consequently, the ID and dementia should be understood as separate clinical entities that need to be taken into account in the health management of intellectually disabled people. This is important for the arrangement of appropriate and timely interventions, which can be expected to delay the need for institutionalization.

A 69-year-old woman with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a rare intellectual disability syndrome classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and other digits, distinctive facial features, hirsutism/hypertrichosis, and sparce scalp hair. It is genetically heterogeneous but most often caused by a pathogenic variant in the ARID1B gene. Previous clinical reports of CSS patients are mainly based on young or middle-aged individuals. Here, we report a 69-year-old woman with CSS phenotype and a pathogenic ARID1B loss-of-function variant c.5259_5260dup. She has severe intellectual disability but otherwise she is in relatively good health both physically and mentally. There is no evident history of chronic illness or progressive disability. CSS appears to be compatible with long survival and most likely it is underdiagnosed in geriatric patients with intellectual disability.

Intellectual disability in patients with epilepsy with eyelid myoclonias.

We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21-53 years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence.

Age at Death in Individuals with Intellectual Disabilities.

BACKGROUND: We aimed to ascertain the average age at death (AD) in the intellectual disability population for each gender and compare them to those of the general population during 1970-2012. METHODS: By analysing medical records, we calculated the ADs of all deceased clients (N = 1236) of two district organizations responsible for intellectual disability services. Statistics Finland's database generated data regarding ADs of all inhabitants who had died after having resided in same district. RESULTS: During the follow-up, average ADs for the intellectual disability population and general population increased, and simultaneously the AD difference between these populations decreased. In the 2000s, the AD difference between the intellectual disability population and the whole population was 22 years for men (95% CI: -24 to -20) and 30 years for women (95% CI: -33 to -27). In 2000s, the mean AD of those with mild-to-moderate intellectual disability (IQ 50-69) for women and men was 56 (SD17) and 54 (SD18), and those with severe to profound intellectual disability (IQ<50), 44 (SD23) and 43 (SD21). CONCLUSIONS: Intellectual disability is still a considerable risk factor for early death. Among the intellectual disability population, unlike in general population, the lifespans of women and men are equal.

Aspartylglycosaminuria: a review.

Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines - aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end - and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.

Mortality in individuals with intellectual disabilities in Finland.

OBJECTIVES: This study aimed at ascertaining the standardized mortality ratios (SMR) for those with an intellectual disability (ID) in Finland. MATERIALS AND METHODS: We used the statistical database of the national insurance institution of Finland and Statistics Finland's mean population figures. We determined the number of individuals who received benefits (disability allowance, disability pension, or care allowance for pensioners) due to an ID diagnosis and the number of those whose benefit had been terminated due to death during the years 1996-2011. RESULTS: SMR for females with a mild ID (IQ 50-69) was 2.8 (95% CI: 2.60-3.01) and for males 2.0 (95% CI: 1.88-2.14), and for females with a severe ID (IQ <50) 5.2 (95% CI: 4.99-5.50) and for males 2.6 (95% CI: 2.48-2.72). CONCLUSION: This significant difference in the SMR figures between males and females with ID warrants further research.