Genetic changes of chromosome region 15q11-q13 in Prader-Willi and Angelman syndromes in Finland

Abstract The Prader-Willi (PWS) and Angelman (AS) syndromes are clinically distinct developmental disorders which are caused by genetic defects in the imprinted domain at chromosome 15q11-q13, resulting in the loss of paternal (PWS) or maternal (AS) gene function. In this study, the genetic changes of 15q11-q13 and their possible inheritance in Finnish PWS (n=76) and AS (n=47) patients are described. The diagnosis could be confirmed by laboratory methods in all PWS and in 43 (91%) AS patients. A deletion of 15q11-q13 accounted for 76% of the PWS and 67% of the AS patients in whom a specific genetic defect had been established. The origin of deletion was always paternal in PWS and maternal in AS. In PWS, deletions of four different sizes were detected, while in AS only type I or II deletions were found. The smallest overlap of deletions/critical region detected was from locus D15S13 to locus D15S10 in PWS and from locus D15S128 to locus D15S12 in AS. A rare recurrence of del(15)(q11q13) due to maternal germ line mosaicism is described. Maternal uniparental disomy of chromosome 15 accounted for 21% of PWS patients and paternal UPD for 2% of AS patients. In PWS, most UPD cases were due to errors in maternal meiosis (87%), most commonly leading to maternal heterodisomy (MI error). In AS, a rare error in the second segregation of paternal meiosis was found. UPD was associated with advanced maternal age, the mean being 34.6 years. Imprinting defects were found in 3% of PWS (two non-IC-deletions) and 11% of AS (IC deletion in one sib pair and three non-IC-deletions) patients. In the case with IC deletion, the mutation was seen in several generations. The non-deletion cases were thought to be due to a de novo prezygotic or postzygotic error. In the non-deletion PWS cases, the maternally imprinted paternal chromosome region was shown to have been inherited from the paternal grandmother, while in AS the paternally imprinted maternal chromosome region had been inherited from either the maternal grandfather or the maternal grandmother. The region of IC involved in AS was defined to be 1.15 kb. Five (11%) AS patients with normal DNA methylation test results had a UBE3A mutation. One of the two novel missense mutations (902A→C) had been inherited from the mosaic mother, while the mutation 975T→C was a new one. De novo deletions 1930delAG and 3093delAAGA have also been described previously, suggesting that these sites may be mutation hotspots in UBE3A. Identification of different genetic aetiologies with different recurrence risks is essential for genetic counselling, and close co-operation between clinicians and the laboratory is required both for diagnosis and for the detection of possible inheritance

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

Abstract 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