Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disorder and a distinctive type of osteopetrosis, characterized mainly by skeletal fractures and deformity, osteosclerosis, and sometimes hypotonia, developmental delay, and seizures. Sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene underlying OSMD have been reported previously. In the present study, we investigated a 14-year-old girl suspected with OSMD in a consanguineous family of Iranian origin segregating the disease in an autosomal-recessive manner. The patient had severe short stature, multiple sclerotic lesions, sandwich vertebrae, Erlenmeyer flask deformity, and looser zones. The multifocal active bony pathology suggested multifocal bony inflammation or multiple looser fractures. Whole-exome sequencing followed by Sanger sequencing confirmation revealed a novel homozygous stop gain mutation (c.G2785T, p.E929X) in the LRRK1 gene. This is the first mutation in the LRRK1 gene, underlying OSMD, in the Iranian population and the third case worldwide.The mutation is located in the C terminal of the Roc domain, distinct from domains affected in the previous two LRRK1 mutations. Additionally, a new group of clinical indications different from the two previous cases is discussed. K E Y W O R D S skeletal dysplasia, LRRK1, whole-exome sequencing 102 How to cite this article: Miryounesi M, Nikfar A, Changi-Ashtiani M, et al. A novel homozygous LRRK1 stop gain mutation in a patient suspected with osteosclerotic metaphyseal dysplasia. Ann Hum Genet.

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Down syndrome or trisomy 21 is the most common genetic disorder with a prevalence of 1 in 700 live-born infants. It is characterized by the intellectual disability of varying range, developmental delay, distinctive facial features and various physical abnormalities. The most frequent clinical features include hypotonia, short stature, short neck, upward slanting eyes, flat nasal bridge, bulging tongue, small ears and a single palmar crease of the hands. Mainly there are three cytogenetic forms of Down syndrome including free trisomy 21, mosaicism and Robertsonian translocation. We describe the case of a 1-year-old Iranian female child who presented to our genetic counseling center with intellectual and physical disabilities. The most common features of Down syndrome were present. The cytogenetic analysis confirmed the diagnosis, with detection of the Robertsonian translocation t(21q; 21q). The patient's parents were found to be both phenotypically and cytogenetically normal, so the identified Robertsonian translocation t(21q; 21q) probably have arisen de novo. © 2019 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran 2019;57(8):522-524.

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Autosomal recessive cutis laxa type 2B (ARCL2B) is a rare genetic connective tissue disorder characterized by wrinkled inelastic skin, intellectual disability, growth retardation, developmental delay, skeletal abnormalities, and facial dysmorphism. Recently, PYCR1, encoding the pyrroline-5-carboxylate reductase 1, was reported as the first gene involved in ARCL2B. In this study, using whole exome sequencing, we identified a homozygous PYCR1 missense mutation, c.722C>A; p.Ala241Asp, in an Iranian male patient. Our report expands the clinical spectrum of PYCR1 mutations. Furthermore, this study shows that whole exome sequencing could serve as a viable diagnostic approach to identify the etiology of rare genetic diseases.