REPORT Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature Rami Abou Jamra, 1,8, * Orianne Philippe, 2,8 Annick Raas-Rothschild, 3 Sebastian H. Eck, 4 Elisabeth Graf, 4 Rebecca Buchert, 1 Guntram Borck, 2 Arif Ekici, 1 Felix F. Brockschmidt, 5,6 Markus M. No ¨then, 5,6 Arnold Munnich, 2 Tim M. Strom, 4,7 Andre Reis, 1,9 and Laurence Colleaux 2,9, * Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disor- ders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected indi- viduals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42*), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542þ1_542þ4delGTAA, r.421_542del, p.Glu181Glyfs*20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolution- arily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4- complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex. With a worldwide prevalence of around 2%, early-onset cognitive impairment, commonly referred to as intellec- tual disability (ID), is the most frequent cause of severe disability and a leading socioeconomic healthcare problem in Western countries. 1 For the last two decades, remarkable progress has been made in the elucidation of ID condi- tions. About 30% percent of severe ID cases have been ascribed to chromosomal imbalances. 2 Defects in X-linked genes account for about 10% of male ID cases. 3 Yet despite these recent advances, the cause of ID remains unex- plained in the majority of cases, and this leaves families without accurate diagnosis or genetic counseling. In partic- ular, very little is known about the autosomal-recessive forms of ID (ARID). The broad genetic heterogeneity of ARID precludes any possibility of pooling families, and the scarcity of large pedigrees suitable for linkage analyses have hitherto hampered identification of the genes responsible for most of these cases. This problem has been successfully circumvented by the use of autozygosity mapping in large consanguineous families; in nonspecific ARID ten genes have been identified so far. 1,4–12 Neverthe- less, mutations in each of these genes only account for one or very few families, suggesting that many genes remain to be identified. Here, we present linkage analyses, mutation discovery, and clinical characterization of a recognizable ARID syndrome in eight affected individuals from three consan- guineous families. Family ID01 is a sibship of three affected and two healthy siblings born to healthy parents, who are second cousins of Israeli–Arab descent (Figure 1A and Table 1). Pregnancy and delivery were unremarkable in all three affected cases. At birth all three siblings presented with microcephaly and muscular hypotonia, which later devel- oped to hypertonia. At the time of examination, a clinical assessment showed hyperreflexia, spastic paraplegia, and an inability to walk unaided. All affected individuals re- vealed a severe cognitive deficit, marked speech delay, and adaptive impairment. Furthermore, they presented with microcephaly, a high palate, mildly remarkable facial gestalt with a wide nasal bridge, short stature, hyperlaxity, genu recurvatum, pes planus, and a waddling gait. All three affected individuals had stereotypic laughter and markedly shy character. None of the patients had seizures, vision or 1 Institute of Human Genetics, University of Erlangen, D-91054 Erlangen, Germany; 2 INSERM U781, Fondation IMAGINE, De ´partement de Ge ´ne ´tique and De ´partement de Radiologie Pe ´diatrique, Universite ´ Paris Descartes, Ho ˆpital Necker-Enfants Malades, 75015 Paris, France; 3 Department of Human Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel; 4 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany; 5 Department of Genomics, Life and Brain Center, University of Bonn, D-53127 Bonn, Germany; 6 Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany; 7 Institute of Human Genetics, Klinikum rechts der Isar, Technische Universita ¨t Mu ¨nchen, D-80634 Mu ¨nchen, Germany 8 These authors contributed equally to this work 9 These authors contributed equally to this work *Correspondence: rami.aboujamra@uk-erlangen.de (R.A.J.), laurence.colleaux@inserm.fr (L.C.) DOI 10.1016/j.ajhg.2011.04.019. Ó2011 by The American Society of Human Genetics. All rights reserved. 788 The American Journal of Human Genetics 88, 788–795, June 10, 2011