RAPID COMMUNICATION OFFICIAL JOURNAL www.hgvs.org Loss of Function Mutation in LARP7, Chaperone of 7SK ncRNA, Causes a Syndrome of Facial Dysmorphism, Intellectual Disability, and Primordial Dwarfism Anas M. Alazami, 1 † Mohammad Al-Owain, 2 † Fatema Alzahrani, 1 Taghreed Shuaib, 1 Hussain Al-Shamrani, 3 Yahya H. Al-Falki, 4 Saleh M. Al-Qahtani, 5 Tarfa Alsheddi, 1 Dilek Colak, 6 and Fowzan S. Alkuraya 1,7,8 ∗ 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 2 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 3 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 4 Division of Ophthalmology, Department of Surgery, King Khalid University, Abha, Saudi Arabia; 5 Department of Pediatrics, King Khalid University, Abha, Saudi Arabia; 6 Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 7 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 8 Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia Communicated by Garry R. Cutting Received 30 March 2012; accepted revised manuscript 19 July 2012. Published online 3 August 2012 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.22175 ABSTRACT: Primordial dwarfism (PD) is a clinically and genetically heterogeneous condition. Various molecular mechanisms are known to underlie the disease including impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA damage response, defective spliceosomal machinery, and abnormal replication licensing. Here, we describe a syndromic form of PD associated with severe intellectual disability and distinct facial features in a large multiplex Saudi family. Analysis reveals a novel under- lying mechanism for PD involving depletion of 7SK, an abundant cellular noncoding RNA (ncRNA), due to mu- tation of its chaperone LARP7. We show that 7SK levels are tightly linked to LARP7 expression across cell lines, and that this chaperone is ubiquitously expressed in the mouse embryo. The 7SK is known to influence the ex- pression of a wide array of genes through its inhibitory effect on the positive transcription elongation factor b (P- TEFb) as well as its competing role in HMGA1-mediated transcriptional regulation. This study documents a criti- cal role played by ncRNA in human development and adds to the growing list of molecular mechanisms that, when perturbed, converge on the PD phenotype. Hum Mutat 00:1–6, 2012. C  2012 Wiley Periodicals, Inc. KEY WORDS: ncRNA; LARP7; RN7SK; primordial dwarfism; HMGA1 Additional Supporting Information may be found in the online version of this article. † These two authors have contributed equally to this work. ∗ Correspondence to: Fowzan S. Alkuraya, Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyad 11211, Saudi Arabia. E-mail: falkuraya@kfshrc.edu.sa Contract grant sponsors: King Faisal Specialist Hospital and Research Centre (RAC no. 2080006); KACST (grant 09-MED941-20 to F.S.A.); DHFMR Collaborative Grant (to F.S.A.). Introduction Primordial dwarfism (PD), as the name indicates, is a clinical phenotype characterized by severe growth restriction that has its onset in utero. The term is usually restricted to cases where all growth parameters are several standards of deviation below the age- adjusted mean and frank skeletal dysplasia is excluded. Phenotypic variation can help define distinct clinical entities, a classification that was corroborated by the molecular delineation of these entities, which proved that they are indeed distinct. For example, relative preservation of the head circumference and asymmetric body in- volvement is the hallmark of Russell–Silver syndrome, whereas se- vere microcephaly and distinct facies typically signify diagnosis of Seckel syndrome. Although other mechanisms have been described, it is now well established that a methylation defect at the 15q11 locus leads to reduced expression of IGF-2 causing severe growth deficiency. The “mirror-image” of this methylation defect, coin- cidentally, is observed in the Beckwith-Wiedemann (overgrowth) syndrome. Seckel syndrome, on the other hand, has proven more complex in etiology with at least five established disease genes in addition to hitherto unsolved linkage loci. ATR controls cell cycle arrest in response to DNA damage and mutations in this gene have been observed at low frequency in Seckel syndrome [O’Driscoll et al., 2003]. RBBP8 and CEP152, both involved in the cellular response to DNA damage, have also been shown very recently to cause the Seckel phenotype [Kalay et al., 2011; Qvist et al., 2011]. In addi- tion, mutations in the centriolar proteins CENPJ and PCNT have been demonstrated to cause Seckel syndrome, presumably through abnormal organization of the centriole/mitotic spindle apparatus [Al-Dosari et al., 2010; Griffith et al., 2008; Rauch et al., 2008]. A closely related phenotype known as microcephalic osteodysplastic primordial dwarfism type II (MOPD II) can also be caused by PCNT mutations [Willems et al., 2010]. Two very recent reports implicated mutations in RNU4ATAC, a component of the spliceosomal machin- ery, as causative of the clinically distinct MOPD type I [Edery et al., 2011; He et al., 2011]. Finally, another form of microcephalic PD known as Meier–Gorlin syndrome was found to be caused by defec- tive components of the prereplication complex, implicating defects in replication licensing [Bicknell et al., 2011a,b]. These molecular defects underlying different forms of PD underscore the complex C  2012 WILEY PERIODICALS, INC.