PMC

(a-d) Pedigrees of four families with syndromic neurodevelopmental symptoms segregating in an autosomal recessive pattern of inheritance. Double lines in pedigrees indicate consanguinity. Filled and unfilled circles/squares represent affected and unaffected individuals respectively, while circle/squares with diagonal lines indicate deceased individuals. Genotypes are represented as either WT/WT (wild type), MX/WT (heterozygous) or MX/MX (homozygous) for individuals with available genotypes.
(e-h) Representative chromatograms are shown for each variant. Vertical arrows indicate variant position.
(i) Top: Schematic of the ZNF142 locus with exons 6–9 harboring likely pathogenic variants. Boxes, exons; black line, introns; white, untranslated regions; blue shaded boxes, coding regions. Bottom: Schematic representation of ZNF142 protein; gray colored rectangles represent predicted C₂H₂-type domains. Truncating alterations are indicated with black lollipops; missense variants are indicated with salmon-colored lollipops.

(a) Stretches of homozygosity were mapped on jointly called ES data from five individuals (two affected, two unaffected siblings, and their unaffected mother) using HomozygosityMapper software. Black vertical lines, regions with <80% homozygosity exclusive to cases; red vertical lines, regions with >80% homozygosity exclusive to cases. The blue arrow indicates a stretch of homozygosity on chr2 harboring the ZNF142 variant.
(b) Enlarged view of chr2 indicating the homozygous genomic stretches shared between affected individuals. The blue dotted rectangle outlines the 10.6 Mb region of interest with a 100% homozygosity score.
(c) Graphical representation of the homozygous region on chr2 generated with Gene distiller. ZNF142 is localized to the homozygous region shared between cases and differs from healthy siblings and their unaffected mother. Black rectangle and flanking hg19 coordinates (red, top) indicate the region containing ZNF142. Blue, heterozygous variant calls; red, homozygous regions with lighter red to darker red reflecting shorter to longer homozygous stretches, respectively.
(d) Ideogram of chr2 generated by Genome Data Viewer showing the position of ZNF142 (blue rectangle) at 2q35 (hg19: chr2: 219502640–219524355).

720 C₂H₂ domain-containing members of zinc finger proteins queried from the HUGO gene nomenclature committee were mapped to protein accession numbers with BioMart. Mapped proteins were used as input for a conserved domain and local sequence similarity multiple protein alignment using COBALT (maximum sequence difference set to 0.85 and using the Grishin distance metric).
(a) 492 mapped proteins are displayed as a Cobalt distance circular map sorted by their structural distance. In addition to ZNF142, proteins with OMIM clinical synopses are marked on the map, along with their designation as involved in neurodevelopmental processes (NDD; blue) or other processes (yellow; see ).
(b) ZNF142 is aligned with the proteins in the adjacent branches of the cladogram and conserved protein domains for the Atrophin-1 family structure and C₂H₂ domain are shown. * denotes proteins without annotations in OMIM, but with support in peer-reviewed literature for an NDD designation.