Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series.

BACKGROUND: Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. METHODS: In-depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first-degree relatives. Risk variants were identified through bioinformatic analysis. RESULTS: One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. CONCLUSION: 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow-up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

Haploinsufficiency of XPO1 and USP34 by a de novo 230 kb deletion in 2p15, in a patient with mild intellectual disability and cranio-facial dysmorphisms.

2p15p16.1-deletion syndrome was first described in 2007 based on the clinical presentation of two patients. The syndrome is characterized by intellectual disability, autism spectrum disorders, microcephaly, dysmorphic facial features and a variety of congenital organ defects. The precise genotype-phenotype correlation in 2p15-deletion syndrome is not understood. However, greater insight can be obtained by thorough clinical investigation of patients carrying deletions, especially those of small size. We report a 21-year-old male patient with features overlapping the clinical spectrum of the 2p15p16.1-deletion syndrome, such as intellectual disability, dysmorphic facial features, and congenital defects. He carried a 230 kb de novo deletion (chr2:61500346-61733075 bp, hg19), which affects the genes USP34, SNORA70B and XPO1. While there is a lack of functional data on SNORA70B, the involvement of USP34 and XPO1 in the regulation of fundamental developmental processes is well known. We suggest that haploinsufficiency of one or both of these genes is likely to be responsible for the disease in our patient.

Health and disease in adults with Down syndrome.

BACKGROUND: The increasing life expectancy of persons with Down syndrome calls for a knowledge of conditions that frequently occur in adults with the syndrome and of which health personnel should be particularly aware. METHOD: The article is based on a literature search in PubMed and the authors' clinical experience with the patient group. RESULTS: Altered immune system function, muscular hypotonia, dysmorphic otolaryngologic features and premature ageing contribute to health problems. The group is susceptible to infections, particularly of the respiratory and the gastrointestinal tract. Congenital heart defects may give rise to symptoms, also in adults. Many also develop mitral valve disease, including those without congenital heart defects. Hypothyroidism develops in up to half, and coeliac disease in one of five. Obstructive sleep apnoea syndrome occurs in approximately half. Sensorineural hearing loss and cataract may occur before the age of 30. Atlantoaxial instability occurs, and radiological examination of the neck must take place before intervention under general anaesthesia. Behavioural changes with loss of skills, withdrawal, psychomotoric retardation and mutism occur frequently from the age of 30 and may be symptoms of mental illness or the onset of Alzheimer's dementia. INTERPRETATION: Adults with Down syndrome need to undergo regular medical examinations, and we recommend an annual check-up with the primary doctor. Screening for hearing loss and cataract is also recommended every three and five years, respectively. In the event of concomitant symptoms, particularly related to neurological and psychiatric conditions, the patient can be referred to the habilitation service.