Methods
A questionnaire filled out by the patient’s clinical team was used to
collect detailed clinical characteristics of affected individuals with
bi-allelic EIF3F variants. To normalize body measurements
(height, weight and head circumference) to the corresponding age, the
publicly available data-source “https://www.pedz.de/” based on birth
data by Voigt et al. (2006) and studies reported by Kromeyer-Hauschild
et al. for older age groups (2001) were used.
EIF3F variants were identified by sequencing of autism/
intellectual disability gene panels, whole exome sequencing (WES) or
whole genome sequencing, performed as a clinical test or within a
research project, or by Sanger sequencing for co-segregation testing in
core family members, as presented in Supportive Table 1.
We used genotypes of 136 frequent SNPs (MAF >5%) generated
from internal WES data (1,818 independent samples, affected individual
and parents of P13 and one affected individual of P14) coveringEIF3F and its flanking regions (chr11:7,614,107-8,413,933
(hg19)). We defined haplotype blocks using the definition of the model
“solid spine of linkage disequilibrium (LD)” in Haploview (Barrett,
Fry, Maller, & Daly, 2005) and determined haplotypes at an individual
basis using PHASE vs.2.1.1 (Stephens, Smith, & Donnelly, 2001) as
described previously (Huffmeier et al., 2009). Within the LD block ofEIF3F , five of seven common SNPs (rs79714374, rs12421289,
rs12278319, rs7941782, rs4758267, rs12420464, rs56392532) were
identified to be tagging SNPs for six different haplotypes with
frequencies between 3.5-53.4%. The set of seven SNP was used to assess
the haplotypes in other affected individuals with the homozygousEIF3F missense variant and if available, their parents (11/12).
Some redundantly tagged SNPs (rs79714374 and rs56392532) had a coverage
of <10x in affected individuals of P2, P3, P6, P10, P12, P17
(Table 2), but due to very high linkage disequilibrium in 1,818 WES,
their genotypes could be tagged by rs12420464 and rs12421289,
respectively. Genotypes of rs12278319 in mother of P10 and of rs79714374
and rs12420464 in the affected individual of P17 could be inferred in
single individuals of P10, P17 due to available genotypes in other core
family members, and the ones of two SNPs in P4 (rs79714374, rs12420464)
could be deduced to one of the haplotypes identified in 1,818 WES data.