REPORT Neu-Laxova Syndrome, an Inborn Error of Serine Metabolism, Is Caused by Mutations in PHGDH Ranad Shaheen, 1 Zuhair Rahbeeni, 2 Amal Alhashem, 4 Eissa Faqeih, 3 Qi Zhao, 5 Yong Xiong, 5 Agaadir Almoisheer, 1 Sarah M. Al-Qattan, 1 Halima A. Almadani, 8 Noufa Al-Onazi, 4 Badi S. Al-Baqawi, 6 Mohammad Ali Saleh, 3 and Fowzan S. Alkuraya 1,7, * Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite exten- sive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities. Neu-Laxova syndrome (NLS [MIM 256520]) is a term coined by Lazjuk in 1979 to unify the independent reports by Neu and Laxova on a lethal multiple-congenital- anomaly syndrome. 1–3 The main features of NLS involve defective somatic growth and CNS and skin development, in addition to many other anomalies that might represent primary malformations or a malformation sequence. Growth restriction is a constant feature that is usually apparent in the second trimester, and it could be argued that NLS could be classified as a primordial dwarfism dis- order, especially given that frank skeletal dysplasia is un- common in this condition. 4 Another constant feature is abnormal brain development, most commonly in the form of profound microcephaly; a head circumference of 20 cm at term has been reported. 5,6 Most of the case reports that describe detailed brain examination by imaging or on autopsy converge on a highly characteristic phenotype of the brain. In addition to being extremely small in volume, the brain has a distinctive pattern of lissencephaly, which some label as lissencephaly type III to differentiate it from type I, seen in Miller-Dieker syndrome (MIM 247200), and the cobblestone type II, seen in Walker-Warburg syndrome (MIM 236670) and related disorders of glycosylation. The cerebellum is often hypoplastic, and complete absence of the vermis has frequently been reported. In addition, the corticomedullary tracts are often small or absent in the brainstem and spinal cord. 5 It has been proposed that in view of the severity of CNS involvement, the skeletal manifestations in the form of contractures and syndactyly represent a sequence that is initiated by the brain malfor- mation labeled as cerebroarthrodigital (CAD) sequence. 7 Contractures, which are common in NLS and sometimes accompanied by pterygium formation, are associated with hypoplasia of the skeletal muscles. Syndactyly of the hands and feet often takes an unusual form of severe swelling and rudimentary digits that are sometimes un- discernible. 8 The skin is usually ichthyotic with marked hyperkeratosis and can resemble the colloidon membrane appearance of other ichthyotic disorders. 9 The face is highly characteristic with proptotic eyes, ectropion, ecla- bion, and a severely hypoplastic nose. Most affected chil- dren die shortly after birth, although survival beyond 10 months has been reported and presumed to represent a milder phenotype. 10 The nature of this extremely severe multiple-congen- ital-anomaly syndrome has been debated for decades. In addition to the CAD sequence theory above, another proposal is that NLS might represent an inborn error of fat metabolism. 8 The latter was prompted by the often reported finding of significant accumulation of fat and myxoedematous material in the dermis throughout the body; this accumulation gives the typical edematous appearance of affected fetuses, who are sometimes referred to as being ‘‘hydropic.’’ 11 In this study, we took advantage of the powerful tools of autozygosity mapping and whole-exome sequencing to show that NLS is in fact an inborn error of serine metabolism and that a mouse model recapitulating key neurological and other features 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; 2 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; 3 Department of Pediatrics, King Fahad Medical City, Riyadh 59046, Saudi Arabia; 4 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia; 5 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; 6 Maternal Fetal Department, Women’s Specialist Hospital, King Fahad Medical City, Riyadh 59046, Saudi Ara- bia; 7 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; 8 Pediatric metabolic laboratory, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia *Correspondence: falkuraya@kfshrc.edu.sa http://dx.doi.org/10.1016/j.ajhg.2014.04.015. Ó2014 by The American Society of Human Genetics. All rights reserved. 898 The American Journal of Human Genetics 94, 898–904, June 5, 2014