ABSTRACT
By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
Subject(s)
Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Dwarfism/genetics , Genetic Variation , Intellectual Disability/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Musculoskeletal Abnormalities/genetics , Body Height , Child , Exome , Face , Female , Genetic Association Studies , Germ-Line Mutation , Haploinsufficiency , Histones/chemistry , Humans , Male , Mutation, Missense , PhenotypeABSTRACT
PURPOSE: The interpretation of genetic variants after genome-wide analysis is complex in heterogeneous disorders such as intellectual disability (ID). We investigate whether algorithms can be used to detect if a facial gestalt is present for three novel ID syndromes and if these techniques can help interpret variants of uncertain significance. METHODS: Facial features were extracted from photos of ID patients harboring a pathogenic variant in three novel ID genes (PACS1, PPM1D, and PHIP) using algorithms that model human facial dysmorphism, and facial recognition. The resulting features were combined into a hybrid model to compare the three cohorts against a background ID population. RESULTS: We validated our model using images from 71 individuals with Koolen-de Vries syndrome, and then show that facial gestalts are present for individuals with a pathogenic variant in PACS1 (p = 8 × 10-4), PPM1D (p = 4.65 × 10-2), and PHIP (p = 6.3 × 10-3). Moreover, two individuals with a de novo missense variant of uncertain significance in PHIP have significant similarity to the expected facial phenotype of PHIP patients (p < 1.52 × 10-2). CONCLUSION: Our results show that analysis of facial photos can be used to detect previously unknown facial gestalts for novel ID syndromes, which will facilitate both clinical and molecular diagnosis of rare and novel syndromes.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Craniofacial Abnormalities/genetics , Genomics , Intellectual Disability/diagnosis , Muscular Atrophy/genetics , Neurodevelopmental Disorders/diagnosis , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Algorithms , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/physiopathology , Facial Recognition , Female , Humans , Image Processing, Computer-Assisted , Infant , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Intracellular Signaling Peptides and Proteins/genetics , Male , Middle Aged , Muscular Atrophy/diagnosis , Muscular Atrophy/physiopathology , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/physiopathology , Mutation, Missense/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/physiopathology , Phenotype , Protein Phosphatase 2C/genetics , Vesicular Transport Proteins/genetics , Young AdultABSTRACT
The Koolen-de Vries syndrome (KdVS) is a multisystem syndrome with variable facial features caused by a 17q21.31 microdeletion or KANSL1 truncating variant. As the facial gestalt of KdVS has resemblance with the gestalt of the 22q11.2 deletion syndrome (22q11.2DS), we assessed whether our previously described hybrid quantitative facial phenotyping algorithm could distinguish between these two syndromes, and whether there is a facial difference between the molecular KdVS subtypes. We applied our algorithm to 2D photographs of 97 patients with KdVS (78 microdeletions, 19 truncating variants (likely) causing KdVS) and 48 patients with 22q11.2DS as well as age, gender and ethnicity matched controls with intellectual disability (n = 145). The facial gestalts of KdVS and 22q11.2DS were both recognisable through significant clustering by the hybrid model, yet different from one another (p = 7.5 × 10-10 and p = 0.0052, respectively). Furthermore, the facial gestalts of KdVS caused by a 17q21.31 microdeletion and KANSL1 truncating variant (likely) causing KdVS were indistinguishable (p = 0.981 and p = 0.130). Further application to three patients with a variant of unknown significance in KANSL1 showed that these faces do not match KdVS. Our data highlight quantitative facial phenotyping not only as a powerful tool to distinguish syndromes with overlapping facial dysmorphisms but also to establish pathogenicity of variants of unknown clinical significance.