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.
Objective: We aimed to evaluate whether there is a significant association between a placental pathology diagnosis basal plate myofibers (BPMF) in an index pregnancy with PAS in the subsequent pregnancy.
Study design: We conducted a retrospective nested cohort study of all cases with a histopathologic finding of BPMF between August 2012 and March 2020 at a single tertiary referral center. Data were collected for all subjects (cases and controls) with at least two consecutive pregnancies (the initial index pregnancy and at least one subsequent pregnancy) accompanied by a concomitant record of histopathologic study of the placenta at our center. The primary outcome was pathologically confirmed PAS in the subsequent pregnancy. Data are presented as percentage or median, interquartile range (IQR) accordingly.
Results: A total of n=1,344 participants were included, of which n=119 (index cases) carried a contemporaneous histopathologic diagnosis of BPMF during the index pregnancy and n=1,225 did not (index controls). Among the index cases, patients with BPMF were older (31.0 [20, 42] vs 29.0 [15, 43], p <0.001), more likely to have undergone IVF for conception (10.9% vs 3.8%, p=0.001) and were of a more advanced gestational age at delivery (39.0 [25, 41] vs 38.0 [20, 42], p=0.006). In the subsequent pregnancy, the rate of PAS was significantly higher among the BPMF index cases (6.7% versus 1.1%, p<0.001). After adjusting for maternal age and IVF, a histopathologic diagnosis of BPMF in an index pregnancy was shown to be a significant risk factor for PAS in the subsequent gestation (HR 5.67 [95% CI: 2.28, 14.06], p <0.001).
Conclusion: Our findings support that a histopathologic diagnosis of BPMF is an independent risk factor for PAS in the subsequent pregnancy.
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