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Variants in the mitochondrial alanyl-tRNA synthetase 2 gene AARS2 (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous AARS2 variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive AARS2 variants and further defines the phenotypic spectrum associated with this gene., (© 2019 Kiraly-Borri et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region., Methods: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues., Results: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects., Conclusion: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Oculodentodigital dysplasia (ODDD) is a clinically variable genetic disorder caused by mutations of the GJA1 gene, predominantly inherited in an autosomal dominant fashion. In rare cases ODDD can also exhibit autosomal recessive mode of inheritance. The phenotype of ODDD comprises craniofacial (short and narrow palpebral fissure, thin, narrow nose with hypoplastic alae nasi), dental (oligodontia, hypoplastic enamel), and digital abnormalities (syndactyly of finger 4/5, hypoplastic phalanges). Ocular manifestation is typical and involves microphthalmia, microcornea, glaucoma, congenital malformations of iris or vitreous, ectopic pupils or strabismus. To date, only 67 GJA1 mutations have been described to underlie ODDD and most of them (i.e. 97%) represent missense substitutions. In this report, we describe three (two familial and one sporadic) non-consanguineous cases presenting with ODDD features in whom we identified novel missense heterozygous mutations of the GJA1 gene: c.317T>G (p. L106R), c.G139C (p.D47H), and c.C257A (p.S86Y). The first two mutations were inherited from an affected parent, whereas the latter one occurred de novo. The mutations affect highly conserved amino acid residues located in the different portions of the GJA1 protein. Our report broadens the spectrum of probably pathogenic mutations associated with ODDD phenotype and demonstrates that the amino acid substitutions at highly conserved positions 47, 86, 106 may affect protein functioning and lead to the development of this syndrome. Together with molecular data, we provide a brief clinical description of the affected individuals., (Copyright © 2014 Elsevier B.V. All rights reserved.)