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Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-L-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum.Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor. K E Y W O R D S developmental delay, pilocytic astrocytoma, prenatal ultrasound, PRMT7, systemic venous anomaly 1 | INTRODUCTION In 2015, Akawi et al. (2015) described six affected individuals from three families with variants in the protein arginine methyltransferase 7 (PRMT7) gene. The patients were part of a cohort of 4,125 families analyzed according to probabilistic genotype and phenotype matching, which gave rise to new genes. The associated clinical phenotype seen in these patients was considered a phenocopy of pseudohypoparathyroidism (PHP; MIM 103580; also known as Albright hereditary osteodystrophy. In 2017, Kernohan et al. (2017) reported a 6-year-old male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism, and seizures who was diagnosed with a homozygous 15,309 bp deletion encompassing the transcription start site of the PRMT7 gene. Agolini et al. (2018) described three additional patients with severe/moderate intellectual disability, short stature, brachydactyly, and mild dysmorphic features. Recently, Valenzuela et al. (2018) described a 2-yearold girl with intellectual disability, facial dysmorphism, short stature,brachydactyly, and hearing loss with two mutations inPRMT7. In this report, we describe, the prenatal, postnatal, and pathological findings of two male sibs found to harbor a homozygous PRMT7 mutation. | PATIENTS AND METHODSThis is a retrospective analysis of data from two consecutiv...

Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes.