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Multicenter Study
. 2015 Nov;47(11):1363-9.
doi: 10.1038/ng.3410. Epub 2015 Oct 5.

Discovery of Four Recessive Developmental Disorders Using Probabilistic Genotype and Phenotype Matching Among 4,125 Families

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Free PMC article
Multicenter Study

Discovery of Four Recessive Developmental Disorders Using Probabilistic Genotype and Phenotype Matching Among 4,125 Families

Nadia Akawi et al. Nat Genet. .
Free PMC article

Abstract

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Conflict of interest statement

Competing financial interests

MEH is a consultant for and shareholder in Congenica Ltd, which provides genetic diagnostic services

Figures

Figure 1
Figure 1. Overview of analytical strategy
Figure 2
Figure 2. Clinical and neuroradiological features associated with biallelic variants in KIAA0586
A. Family structures, genotypes and phenotype key of the six families of the affected individuals with biallelic mutations in KIAA0586. The DECIPHER ID is given above and to the left of the pedigree symbol for each affected individual recruited to the DDD study. NT indicates an unaffected individual who has not been tested from the family mutations in KIAA0586. Where available an anterio-posterior (AP) facial photographs and a transverse section from the brain MR is given below the family tree. The white dashed box and white lines indicate the expanded region of the same image illustrating the “molar tooth” shape of the brainstem that is considered characteristic of Joubert syndrome in Families 1, 2, 4 and 5. In family 6 the brainstem shape is atypical for Joubert syndrome. The DECIPHER ID is indicated in all images. Informed consent was obtained to publish photographs. B. A cartoon depicting the protein domain structure of KIAA0586 (1533 aa) encompassing TALPID3 chain (100-1,343; in blue), which includes a highly conserved Region (467 – 554 aa; in orange) required for centrosomal localization and two coiled-coil (182-232 & 467-501 aa; in yellow) domains. A red asterix (coding region variant) or dashed line (essential splice site) is used to indicate the position of each pathogenic mutations identified in the families above.
Figure 3
Figure 3. Clinical and neuroradiological features associated with biallelic variants in HACE1
A. Family structures and genotypes of four families. The DECIPHER ID is given for each recruited affected individual. NT indicates an individual who has not been tested from the family mutations in HACE1. Where available an anterio-posterior (AP) facial photographs and a transverse section from the brain MR is given below the family tree. The elder sibling in Family 4 is also recruited to DDD but on recruitment was considered to have a different disorder from his brother, primary microcephaly. Where available photographs of the face, hands and feet are presented. Saggital and transverse sections from the brain MR is given below the family tree. The saggital images show hypoplasia of the corpus callosum and the transverse images show an apparently reduced brain volume due to paucity of white matter. Informed consent was obtained to publish photographs. B. Protein domain structure of HACE1 (909 aa) encompassing 6 Ankyrin repeats (in orange) and 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain (574 – 909 aa; in blue). A red asterix indicates the position of each pathogenic mutation. C. Prediction of mutation consequence on tertiary protein structure based on PDB IDs: 4bbn and 3tug. The HECT domain is highly conserved and all models share the same fold. The deletion of Leu 832 has significant effect on the fold of the protein. This mutation disrupts the helix by perturbing the hydrophobic core of the domain. This suggests that the mutated protein (ΔLeu832) is unlikely to have the same fold.
Figure 4
Figure 4. Features associated with biallelic variants in MMP21/Mmp21 in humans and mice
A. Pedigrees and genotypes of two families, with DECIPHER IDs. Photograph showing mild craniofacial dysmorphisms including hypoplasia of the malar region and supraorbital ridges and prominent lips. Informed consent was obtained to publish the photograph. B. Modeling of the effect of variants on the tertiary structure of MMP21, based on PDB IDs 1Y93 and 1FBL. Wildtype and mutated residues shown in cyan. The His283Tyr mutation severely reduces Zn2+ binding. The Ile285Thr mutation causes loss of hydrophobicity and weaker interactions with neighbouring non-polar amino acids (green) and should cause movements of surrounding residues potentially leading to conformational shifts that affect Zn2+ binding. C. Protein structure (569aa) encompassing signal peptide (1-24 aa; in orange), propeptide (25- 144 aa; in grey) and matrix metalloproteinase-21 chain (145 – 569 aa; in blue) that includes 4 Hemopexin repeats, with the positions of the human mutations shown above, and positions of ENU-induced mutations in mice shown below. D. Necropsy picture of a Miri mutant with dextrocardia with anterior positioning of the aorta (Ao), indicating transposition of the great arteries (TGA), right lung isomerism, inverted liver lobation (1-3), and dextrogastria (Stm). Confocal episcopic microscopy showed: Miri mutant exhibiting dextrocardia with TGA (E) and atrioventricular septal defect (AVSD) (F), Koli mutant with double outlet right ventricle (G), Miri mutant with dextrocardia with TGA and hypoplastic right ventricle (H), mutant with anomalous right subclavian artery from pulmonary trunk (I), and mutant with duplicated inferior vena cava (IVC) draining into bilaterally symmetric right atria, indicating right atrial isomerism (J).
Figure 5
Figure 5. Features associated with biallelic variants in PRMT7/Prmt7 in humans and mice
A. Pedigrees and genotypes of three families. The DECIPHER ID is given for each recruited affected individual. The father in Family 3 had a cleft lip which is thought to be coincidental. AP facial photographs of the affected individuals are given below the pedigrees. In Family 2 and 3 pictures of the foot show shortened posterior metatarsals. In Family 3 a photo of the hand of an affected individual shows brachydactyly with short metacarpals. Informed consent was obtained to publish photographs. B. Protein domain structure of PRMT7 (692 aa) encompassing two active S-adenosylmethionine-dependent methyltransferases (SAM or AdoMet-MTase) PRMT-type domains (14 – 345 aa; in blue & 358 – 684 aa; in orange). Red asterixes indicate the positions of pathogenic mutations. C. Data derived from mice homozygous for a targeted inactivation of Prmt7 (null; Prmt7tm1a/tm1a). DEXA scanning at 14 weeks of age indicates: female null mice have a reduced bone mineral content (top left graph), both male and female null mice have elevated fat mass (as a percentage of total body mass; top right graph) and reduced body length as determined by distance from nose to the base of the tail (bottom right graph). X-Ray images from 14 week old mice show that the length of the 5th metacarpal was reduced in female null mice only. Box-and-whiskers plots show min-mean-max values. P-values presented are either global adjusted p-values for genotype, or (for sexual dimorphism) the p-value for the interaction between sex and genotype.

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