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. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Am J Med Genet A. 2018 Apr 25;176(6):1375–1388. doi: 10.1002/ajmg.a.38710

XLID Update 2017

Giovanni Neri 1,2, Charles E Schwartz 1, Hebert A Lubs 1, Roger E Stevenson 1
PMCID: PMC6049830  NIHMSID: NIHMS954600  PMID: 29696803

Abstract

The X-chromosome comprises only about 5 percent of the human genome but accounts for about 15 percent of the genes currently known to be associated with intellectual disability. The early progress in identifying the XLID-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96 percent from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function.

Keywords: X chromosome, intellectual disability, syndrome, genes, XLID

Introduction

Over the last three decades there has been remarkable progress in the understanding of X-linked intellectual disability (XLID). The X chromosome was targeted for study because of the excess of males among all individuals with intellectually disability (ID) and the availability of numerous families in which ID followed an X-linked pattern of inheritance. Milestones in the early history of XLID were the study of Penrose (1938) on institutionalized individuals, the description of large XLID families by Martin and Bell (1943), Allan et al. (1944) and Renpenning et al. (1962) and subsequent work by Lehrke (1972). Additional strong motivation came from the notion that the X-chromosome might harbor a disproportionate fraction of genes that influence cognitive function (Turner and Partington 1991) and the discovery of the Fragile X syndrome (a posteriori, rediscovery of the Martin-Bell syndrome), the first XLID entity to be regionally mapped to the X-chromosome (Lubs 1969).

Looking back at previous XLID updates published regularly every two years from 1990 to 2000 and again in 2008, it is apparent that great efforts went into classifying conditions whose phenotypes could not be more diverse. Eventually, these efforts failed, with the exception of the distinction of syndromal from nonsyndromal XLID. Even though the line dividing the two classes is blurred, sometimes arbitrary and difficult to defend from a biological standpoint, it has by now acquired quasi-historical value and deserves to be retained. In compiling the current update, no effort was made to categorize conditions and associated genes. In the practical terms of diagnosis and counseling, what is important is to know the causal genes, the mode of transmission and possibly the pathogenic mechanism.

XLID update 2017 includes the enumeration of all currently known syndromes, nonsyndromal conditions (IDX), and genes, with particular attention to the syndromes described and genes assigned since the 2007 XLID update (Chiurazzi et al. 2008). The discovery of XLID genes has, in large measure, moved from the research laboratory to the diagnostic laboratory during the past decade. Linkage analysis and candidate gene testing has been replaced with X-chromosome or exome sequencing. Various microarray technologies have identified duplications of all XLID genes, bringing attention to genomic aberrations that may even outnumber gene sequence variants. A section of this update, not present in previous editions, describes these duplications and comments on their relevance.

Finding the outstanding causal genes, possibly as many as 80, should complete the delineation of XLID at the genetic/genomic level. This may require utilizing newly emerging technologies – higher resolution microarrays, genome and RNA sequencing, metabolomics and epigenomics.

New Entries

Since the last update in 2007, 69 new XLID genes have been reported in the literature (Table I). Most of these have been associated with syndromal entities, both previously reported and novel. The identified 69 XLID genes may actually be less. As pointed out by Piton et al. (2013), for three genes (MAGT1, RAB40AL, NXF5) the databases utilized as “controls” contain too many loss of function mutations. For three other genes (RPL10, ZMYM3, SIZN1), there have been only a single report so that their inclusion as XLID genes needs replication in additional studies, as further discussed below.

Table I. XLID genes identified 2007-2017.

Year Gene
Symbol		 Gene Name Locus Gene
OMIM		 How
Discovered		 Clinical Description Function References
2007 BRWD3 BROMODOMAIN- AND WD REPEAT-CONTAINING PROTEIN 3 Xq21.1 300553 X-seq XLID-Macrocephaly-Large Ears, IDX93 Transcription factor Field et al. 2007
2007 CUL4B CULLIN 4B Xq24 300304 X-seq XLID-Hypogonadism-Tremor Cell cycle, ubiquitin cycle, E3 ubiquitin ligase Tarpey et al. 2007
2007 GRIA3 GLUTAMATE RECEPTOR, IONOTROPIC, AMPA 3 Xq25 305915 Chr-rea, Exp-Arr, X-seq Chiyonobu XLID, IDX94 Signal transduction, ion transport, glutamate signaling pathway Wu et al. 2007
2007 HSD17B10 (HADH2) 17-BETA-HYDROXYSTEROID DEHYDROGENASE X Xp11.22 300256 L-can XLID-Choreoathetosis Lipid metabolism Lenski et al. 2007
2007 MED12 (HOPA) MEDIATOR COMPLEX SUBUNIT 12NOTE: MEDIATOR COMPLEX SUBUNIT 12 Xq13.1 300188 L-can Opitz FG, Lujan, IDX67 Transcription regulation, RNA polymerase II transcription mediator activity, ligand-dependent nuclear receptor transcription coactivator activity, vitamin D receptor and thyroid hormone receptor binding Risheg et al. 2007
2007 NDUFA1 NADH-UBIQUINONE OXIDOREDUCTASE 1 ALPHA SUBCOMPLEX, 1 Xq24 300078 Mol-Fu Mitochondrial Complex 1 Deficiency Energy production, oxidoreductase activity Fernandez-Moreira et al. 2007
2007 NXF5 * NUCLEAR RNA EXPORT FACTOR 5 Xq22.1 300319 Chr-rea XLID-Short Stature-Muscle Wasting mRNA processing, mRNA export from nucleus Froyen et al. 2007
2007 PORCN PORCUPINE, DROSOPHILA, HOMOLOG Xp11.23 300651 Chr-rea (del) Goltz Wnt receptor signaling pathway, acyltransferase activity, integral to membrane of endoplasmic reticulum Wang et al. 2007
2007 PRPS1 PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I Xq22.3 311850 L-can Arts, PRPS1 Superactivity Ribonucleotide monophosphate biosynthesis de Brouwer et al. 2007
2007 RPL10 * RIBOSOMAL PROTEIN L10 Xq28 312173 X-seq Autism Protein synthesis, ribosomal protein Klauck et al. 2006
2007 UPF3B UPF3, YEAST, HOMOLOG OF, B Xq24 300298 X-seq Lujan/FG Phenotype, IDX62 mRNA catabolism, nonsense-mediated decay Tarpey et al. 2007
2007 ZDHHC9 ZINC FINGER DHHC DOMAIN-CONTAINING PROTEIN 9 Xq26.1 300646 X-seq XLID-Macrocephaly-Marfanoid Habitus Raymond et al. 2007
2008 HUWE1 HECT, UBA, AND WWE DOMAINS-CONTAINING PROTEIN 1 Xp11.22 300697 CMA XLID-Macrocephaly, Juberg-Marsidi-Brooks, IDX17, IDX31 Ubiquitin-protein ligase, mRNA transport Froyen et al. 2008
2008 PCDH19 PROTOCADHERIN 19 Xq22.1 300460 L-can Epilepsy-Intellectual Disability Limited to Females Dibbens et al. 2008
2008 SLC9A6 SOLUTE CARRIER FAMILY 9, MEMBER 6 Xq26.3 300231 L-can Christianson, X-linked Angelman-like Sodium-hydrogen antiporter activity, lysosome organization and biogenesis, regulation of endosome volume Gilfillan et al. 2008
2008 SIZN1 *(ZCCHC12) SMAD-INTERACTING ZINC FINGER PROTEIN 1 Xq24 300701 L-can IDX Modulates BMP signalling influences forebrain cholinergic neurons Cho et al. 2008
2009 MAGT1 * MAGNESIUM TRANSPORTER 1 Xq21.1 300715 L-can, X-seq IDX95 Magnesium transporter with N-glycosylation sites and putative phosphorylation sites Molinari et al. 2008
2009 MBTPS2 MEMBRANE-BOUND TRANSCRIPTION FACTOR PROTEASE, SITE 2 Xp22.12 300294 L-can Ichthyosis Follicularis, Atrichia, Photophobia (IFAP) Protease activity, activates signaling proteins Oeffner et al. 2009
2009 NSDHL NAD(P)H STEROID DEHYDROGENASE-LIKE PROTEIN Xq28 300275 L-can CK (microcephaly, pachygyria, facial dysmorphism, seizures), also in CHILD syndrome Sterol metabolism du Souich et al. 2009
2009 SYP SYNAPTOPHYSIN Xp11.23 313475 X-seq IDX96 Membrane protein of small synaptic vesicles Tarpey et al. 2009
2009 ZNF711 ZINC FINGER PROTEIN 711 Xq21.1 314990 X-seq IDX97 Binds to a subset of PHF8 target genes Tarpey et al. 2009
2010 IQSEC2 IQ MOTIF- AND SEC7 DOMAIN-CONTAINING PROTEIN 2 Xp11.22 300522 X-seq IDX1, IDX18, and other Nonsyndromal XLID Regulation of vesicular transport and organelle structure Shoubridge et al. 2010
2010 PTCHD1 PATCHED DOMAIN-CONTAINING PROTEIN 1 Xp22.11 300828 CMA Autism-XLID Transmembrane protein related to hedgehog receptors Noor et al. 2010
2010 RAB39B RAS-ASSOCIATED PROTEIN Xq28 300774 L-can XLID-Macrocephaly-Seizures -Autism, Waisman-Laxova, IDX72 Formation and maintenance of synapse Giannandrea et al. 2010
2011 CLCN4 CHLORIDE CHANNEL 4 Xp22.2 302910 X-seq IDX15, IDX49 Chloride transport Veeramah et al. 2013
2011 CNKSR2 CONNECTOR ENHANCER OF KSR 2 Xp22.12 300724 CMA XLID-Microcephaly-Seizures Stimulates MAPK signalling Houge et al. 2012
2011 EIF2S3 EUKARYOTIC TRANSLATION INITIATION FACTOR 2, SUBUNIT 3 Xp22.11 300161 X-seq MEHMO Initiates translation Borck et al. 2012
2011 HCFC1 HOST CELL FACTOR C1 Xq28 300019 X-seq IDX3 Cell proliferation Huang et al. 2012
2011 HDAC6 HISTONE DEACETYLASE 6 Xp11.23 300272 L-can Chassaing-Lacombe Chondrodysplasia Tubulin deacetylase Simon et al. 2010
2011 HDAC8 HISTONE DEACETYLASE 8 Xq13.1 300269 Mol-Fu, X-seq Cornelia de Lange, X-linked Chromatin cohesion Deardorff et al. 2012; Harakalova et al. 2012
2011 LAS1L LAS1-LIKE RIBOSOME BIOGENESIS FACTOR Xq12 300964 X-seq Wilson-Turner Nucleolar protein, cell proliferation and ribosome biogenesis Hu et al. 2016
2011 NAA10 N-ALPHA-ACETYLTRANSFERASE 10, NatA CATALYTIC SUBUNIT Xq28 300013 X-seq N-Alpha-Acetyltransferase Deficiency N-terminal acetylation Rope et al. 2011
2011 RAB40AL RAS-ASSOCIATED PROTEIN RAB40A-LIKE Xq22.1 300405 X-seq Martin-Probst (?) Questioned: Hum Mutat 35:1171, 2014 Ras-like GTPase protein Bedoyan et al. 2012
2011 RBM10 RNA-BINDING MOTIF PROTEIN 10 Xp11.3 300080 X-seq TARP RNA-binding Johnston et al. 2014
2011 THOC2 THO COMPLEX, SUBUNIT 2 Xq25 300395 X-seq IDX12, IDX35 mRNA transcription or export Kumar et al. 2015
2012 AIFM1 APOPTOSIS-INDUCING FACTOR, MITOCHONDRIA-ASSOCIATED, 1 Xq26.1 300169 X-seq Charcot-Marie-Tooth disease, Cowchock variant and XLID-spondyloepimetaphyseal dysplasia Induces apoptosis Rinaldi et al. 2012
2012 ALG13 ALG13, S. CEREVISIAE, HOMOLOG Xq23 300776 WES CDG1s Glycosylation Timal et al. 2012; de Ligt et al. 2012
2012 CCDC22 COILED-COIL DOMAIN-CONTAINING PROTEIN 22 Xp11.23 300859 X-seq Cardiofacioskeletal (like 3C/Ritscher-Schinzel) Unknown Voineagu et al. 2012
2012 CLIC2 * CHLORIDE INTRACELLULAR CHANNEL 2 Xq28 300138 X-seq XLID-Cardiomegaly-Seizures Regulating ryanodine receptor channel activity Takano et al. 2012
2012 EBP EMOPAMIL-BINDING PROTEIN Xp11.23 300205 Met-Fu Variable manifestations but XLID-Aggression in one family Enzyme in cholesterol metabolism Furtado et al. 2010
2012 KDM6A LYSINE-SPECIFIC DEMETHYLASE 6A Xp11.3 300128 Chr-rea Kabuki syndrome 2 Histone demethylase and methyltransferase‎ Lederer et al. 2012
2012 PIGA PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS A PROTEIN Xp22.2 311770 X-seq XLID-Brain iron accumulation Enzyme, signal transduction pathway, adhesion molecules Johnston et al. 2012
2012 TMLHE EPSILON-TRIMETHYLLYSINE HYDROXYLASE Xq28 300777 X-seq Autism-ID Enzyme in carnitine synthesis Celestino-Soper et al. 2011
2013 BCAP31 B-CELL RECEPTOR-ASSOCIATED PROTEIN 31 Xq28 300398 X-seq XLID-microcephaly-dystonia ER & golgi structure and metabolism Cacciagli et al. 2013
2013 SSR4 SIGNAL SEQUENCE RECEPTOR, DELTA Xq28 300090 WES XLID-glycosylation defect Glycosylation Losfeld et al. 2014
2013 WDR45 WD REPEAT-CONTAINING PROTEIN 45 Xp11.23 300526 WES Neurodegeneration with brain iron accumulation-XLID Autophagy and other cellular functions Haack et al. 2012; Saitsu et al. 2013
2013 ZC4H2 ZINC FINGER C4H2 DOMAIN-CONTAINING PROTEIN Xq11.2 300897 WES, Chr-rea, CMA Wieacker-Wolff, Miles-Carpenter Axon guidance Hirata et al. 2013
2014 HMGB3 HIGH MOBILITY GROUP BOX 3 Xq28 300193 WES Microphthalmia 13 DNA replication, transcription, nucleosome assembly Scott et al. 2014
2014 KIF4A KINESIN FAMILY MEMBER 4A Xq13.1 300521 WES IDX100 Moves proteins along microtubule Willemsen et al. 2014
2014 MID2 MIDLINE 2 Xq22.3 300204 L-can, WES IDX101 Enzyme, ubiquity ligase E3 microtubule stabilization Geetha et al. 2014
2014 USP9X UBIQUITIN-SPECIFIC PROTEASE 9, X-LINKED Xp11.4 300072 X-seq IDX99 Neuronal migration growth Homan et al. 2014
2014 ZMYM3 * ZINC FINGER, MYM-TYPE 3 Xq13.1 300061 X-seq XLID-aortic stenosis-hypospadias Component of histone deacetylase-containing multiple protein complexes Philips et al. 2014
2015 KLHL15 KELCH-LIKE 15 Xp22.11 300980 X-seq Mild to moderate cognitive impairment, facial dysmorphism, IDX103 Uncertain Mignon-Ravix et al. 2014
2015 DDX3X DEAD/H BOX 3, X-LINKED Xp11.4 300160 WES Variable cognitive, neurologic and nonneurologic manifestations, IDX102 RNA helicase Snijders Blok et al. 2015
2015 FRMPD4 * FERM AND PDZ DOMAINS-CONTAINING PROTEIN 4 Xp22.2 300838 X-seq XLID-Aphasia-seizures, IDX104 Regulates spine morphogenesis Hu et al. 2016
2015 MSL3 MALE-SPECIFIC LETHAL 3, DROSOPHILA, HOMOLOG Xp22.2 300609 WES MSL3-Related XLID Transcription regulation, chromatin modifier Thevenon et al. 2015
2015 NONO NON-POU DOMAIN-CONTAINING OCTAMER-BINDING PROTEIN Xq13.1 300084 WES Mircsof-Langouët Regulation of transcription (activation, repression, splicing, pre-mRNA processing, RNA transport) Mircsof et al. 2015
2015 RBMX RNA-BINDING MOTIF PROTEIN, X CHROMOSOME Xq26.3 300199 WES Shashi RNA binding Shashi et al. 2015
2015 RLIM (RNF12) RING FINGER PROTEIN, LIM DOMAIN-INTERACTING Xq13.2 300379 X-seq IDX with variable microcephaly, behaviour abnormalities and other manifestation, IDX61 Enzyme, ubiquity ligase E3 Tonne et al. 2015
2015 RNF113A RING FINGER PROTEIN 113A Xq24 300951 WES Trichothiodystrophy 5 Gene regulation, DNA repair Corbett et al. 2015
2015 TAF1 TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD Xq13.1 313650 WGS XLID-Craniofacial-Caudal Key role in initiating transcription O'Rawe et al. 2015
2015 USP27X UBIQUITIN-SPECIFIC PROTEASE 27, X-LINKED Xp11.23 3000975 X-seq Variable cognitive and speech impairment and behavioural abnormalities, IDX105 Peptidase Hu et al. 2016
2016 EFHC2 EF-HAND DOMAIN (C-TERMINAL)-CONTAINING PROTEIN 2 Xp11.3 300817 L-can IDX74 Calcium binding and other unknown functions Startin et al. 2015
2016 GRASP1 GRIP1-ASSOCIATED PROTEIN 1 Xp11.23 300408 X-seq XLID-Short Stature-Spasticity Synaptic function and neuronal connectivity Chiu et al. 2017
2016 HNRNPH2 HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN H2 Xp22.1 300610 WES Bain XLID, Female Limited Nuclear localization Bain et al. 2016
2016 SLC25A5 SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ADENINE NUCLEOTIDE TRANSLOCATOR), MEMBER A5 Xq24 300150 CMA IDX70 Mitochondrial exchange of ADP/ATP Vandewalle et al. 2013
2016 STAG2 STROMAL ANTIGEN 2 Xq25 300826 CMA STAG2-Related XLID Chromatin cohesion Leroy et al. 2016
2017 GPKOW G-PATCH DOMAIN AND KOW MOTIFS Xp11.23 301003 X-seq XLID-Microcephaly-Early lethality Spliceosome component Carroll et al. 2017
2017 OGT O-LINKED N-ACETYLGLUCOSAMINE TRANSFERASE Xq13.2 300255 WES XLID-Faciogenital Post translational modification of nucleocytoplasmic proteins Vaidyanathan et al. 2018
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*

Association with XLID has been challenged (Piton et al. 2013) and not subsequently resolved (n=7)

Chr-rea = chromosome rearrangement

WES = whole exome sequencing

WGS = whole genome sequencing

Exp-Arr = expression array

L-can = linkage and candidate gene testing

CMA = array-comparative genomic hybridization

Met-Fu = exploitation of metabolic alteration

Mol-Fu = exploitation of molecular finding

X-seq = sequencing of X-chromosome exons

Among the remaining 63 XLID validated genes identified since 2007, there are 10 (16%) which are associated with the broad process of transcription and an almost equal number, 8 (13%), are involved with either ubiquitination or metabolism. The ubiquitination category was hardly represented among genes reported prior to 2007. Additionally, there is a large group of genes, 13, whose protein function does not fit clearly into an ontology group either because the function is not yet known (e.g. ZC4H2), or its function is not classified (e.g. HMGB3), or because the function could place it into two separate groups (e.g. STAG2).

With the increased annotation of the genome using both genomic and RNA sequencing, at least 6 XLID genes have been found to have anti-sense transcripts (SYP, PTCHD1, THLHE, USP27X, SLC25A5 and HCFC1). It is quite possible that alterations in the noncoding portions of these genes might adversely affect the function, if there is one, of their anti-sense RNA. This may be true for genes cloned before 2007, including FMR1.

Listing of All Known Genes

All XLID genes known to date (141) are listed by year of discovery in Supplementary Table I (S1). The position on the X chromosome of genes associated with XLID syndromes is depicted in Fig. 1. Perusal of the list calls for some comments and considerations. Three syndromes initially reported as X-linked have been found to be autosomal and have been retired. These are Zollino syndrome, initially believed to be X-linked based on one pedigree and subsequently found to be due to an unbalanced 1;12 translocation (Zollino et al. 1992, 2003), Roifman syndrome, initially reported to be X-linked and subsequently found to be caused by a deletion on 2q (Roifman 1999, Merico et al. 2015), and Wittwer syndrome, initially mapped to Xp22.3 and later found to be caused by an unbalanced 4;17 translocation (Wittwer et al. 1996, Wieland et al. 2014).

Figure 1.

Figure 1

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Regional locations of genes associated with XLID syndromes. Bolded genes have also been associated with nonsyndromal XLID. Genes underlined have been challenged by Piton et al. 2013. Color figure can be viewed in the online issue.

Several syndromes previously listed in XLID updates have been removed because the limited evidence that they have intellectual disability as a primary manifestation or that they are X-linked. These include XLID-retinoschisis (312700), X-linked hypoparathyroidism (307700), Giuffrè-Tsukahara (603438), Hyde-Forster (300064), Homfray seizures-contractures, XLID-precocious puberty, and XLID-thyroid aplasia-cutis verticis gyrata. Two additional syndromes have been removed because they appear to be contiguous gene syndromes (XLID-choroideremia-ectodermal dysplasia and XLID-retinitis pigmentosa).

As alluded to above, in 2013, Piton et al. challenged the validity of 25 of the 106 genes then reported to be associated with XLID. Five of the challenged genes were considered highly questionable, five questionable and fifteen in need of replication. None of the 5 highly questionable gene assignments has been confirmed. Of the 5 questionable genes, only ATP6AP2 has been confirmed. Of the 15 assignments in need of replication, additional cases with MAOA, HCFC1, CCDC22, CNKSR2, KIAA2022, NAA10 and SHROOM4 sequence variants have now been published, leaving 17 of the 25 challenged genes unresolved. These genes are identified by an asterisk (*) in Table S1.

Furthermore, a comment on penetrance is in order. Although 183 conditions are classified as XLID syndromes, it is appropriate to note that not all individuals with one of these diagnoses will have ID. Exemplifying this is the inconsistent or even infrequent occurrence of intellectual disability among individuals with Incontinentia Pigmenti, Dyskeratosis Congenita, Oralfacialdigital I, Duchenne Muscular Dystrophy, Simpson-Golabi-Behmel, Aarskog and Nance-Horan syndromes among others. In similar fashion, the severity of ID may vary considerably within certain syndromes e.g., Pelizaeus-Merzbacher, Hunter and Christian syndromes.

In Fig. 2, a histogram illustrates the growing knowledge of XLID syndromes and respective causal genes from 1988 to date. The number of known syndromes has increased from 83 to 183, and the number of cloned genes associated with XLID syndromes from 5 to 113. If we inspect the last column (but this is also true for the others), the apparent discrepancy between 136 syndromes with gene assigned and only 113 genes cloned, requires an explanation. This is due to the fact that a number of genes were found to be responsible for more than one syndrome. Genes that have been linked to three or more XLID syndromes include PQBP1, ATRX, ARX, FLNA, AP1S2 and MED12. The allelic PQBP1-associated disorders include Renpenning, Sutherland-Hann, Hamel Cerebro-Palato-Cardiac, Golabi-Ito-Hall, and Porteous syndromes, all of which have a degree of phenotypic concordance. Strong phenotypic overlap may also be noted among the entities associated with ATRX variants (Alpha-Thalassemia Intellectual Disability, Chudley-Lowry, Holmes-Gang, Carpenter-Waziri, and Arch Fingerprints-Hypotonia syndromes) and the entities associated with AP1S2 variants (Fried syndrome, XLID-Hydrocephaly-Basal Ganglia Calcifications, and Turner XLID syndrome). This is not the case for ARX variants, which have been found in the disparate phenotypes of Partington syndrome, West syndrome, X-linked lissencephaly with abnormal genitalia, hydranencephaly with abnormal genitalia, Proud syndrome, Ohtahara syndrome as well as nonsyndromal XLID (IDX 29, 32, 33, 36, 38, 43, 54, 76, 87). Similar phenotypic discordance has been found among the FLNA-associated disorders (otopalatodigital I and II syndromes, periventricular heterotopias, spondylometaphyseal dysplasia and Melnick-Needles syndrome) and the MED12-associated disorders (Opitz FG, Lujan, and Ohdo syndromes). As to the mapped and unmapped syndromes, totaling 47, some were described in families now lost to follow-up and do not imply that another 47 genes await discovery. It is quite possible that a number of these syndromes could be explained by genes discovered after their initial description.

Figure 2.

Figure 2

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Progress in identifying XLID syndromes and associated genes, 1988-2017. Color figure can be viewed in the online issue.

As to the families with nonsyndromal XLID which have received IDX numbers, their total is currently 105 (Figure 3). For 67 of these families, the genes have been cloned, 33 have been mapped but the genes have not been identified and 5 have reserved IDX numbers (IDX8, 50, 69, 83 and 86) but have not been published. Twenty-eight of the “IDX genes” in Figure 3 have also been associated with XLID syndromes. Sequence variants in 11 genes (KLF8, AFF2, SLC6A8, NDUFA1, ALG13, SRPX2, ATRX, NLGN3, FGDY, CDKL5, and NLGN4) have been found in families with IDX but in whom IDX numbers were never assigned.

Figure 3.

Figure 3

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Families with nonsyndromal XLID which have received IDX numbers. Their total is currently 105. Linkage limits for IDX families for which the genes have not been identified are shown to the right. Color figure can be viewed in the online issue.

Duplication of Xlid Of Genes

Segmental duplications involving all protein-coding regions of XLID-associated genes on the p and q arms of the X chromosome have been reported. They vary in size from a few kilobases to many megabases and do not cross the centromere. Relative to phenotypic consequences of duplications, their informativeness is inversely proportional to the length and the number of genes encompassed within the duplicated segment. Among those duplications which appear to be clinically important, marked skewing of X-inactivation in females is typical.

Duplication of 137 of the 141 XLID genes have been identified in males and duplications of 4 XLID genes (KDM6A, ZNF674, RBM10, and KLF8) have been found only in females. Typically, in these cases, the entire XLID gene is duplicated, often with complete or partial duplication of adjacent genes. Duplication of KLF8, the XLID gene on the p arm closest to the centromere, has been found only in large duplications that involve the entire p arm (Tuck-Muller et al. 1993).

The phenotypic consequences of duplication of XLID genes are protean. In the first instance, the duplication may be associated with a phenotype identical or similar to that associated with a loss of function mutation or deletion of the gene. Such is the case for duplication of the PLP1 gene which results in Pelizaeus-Merzbacher syndrome. In the second instance, duplication of an XLID gene may result in a distinct phenotype but one quite different from loss of function mutations in the same gene. Duplication of MECP2 appears to be the most common duplication of this type but others include duplication of STAG2, HUWE1 and OCRL (van Esch et al. 2005; Friez et al. 2006, 2016; Froyen et al. 2007, 2008; Leroy et al. 2016). Intermediate between these phenotypic consequences are duplications of the ATRX gene which are associated with some manifestations of the Alpha-Thalassemia Intellectual Disability syndrome (short stature, genital anomalies, intellectual disability, hypotonia) but lack the typical facial features seen with loss of function variants in ATRX (Lugtenberg et al. 2009).

Duplications of certain XLID-associated genes (IKBKG, ARX) and certain X chromosome regions (Xp21.33, Xq21.33) do not appear associated with neurodevelopmental abnormalities although they may be associated with other somatic manifestations (van Asbeck et al. 2014; Popovici et al. 2014; Maurin et al. 2017).

Duplication of PLP1

Sequence variants in the coding or splice site regions of PLP1 are found in less than half of families with Pelizaeus-Merzbacher syndrome. More commonly, the condition is caused by duplications of the entire gene (Mimault et al. 1999; Regis et al. 2008). The severity of the signs and symptoms – nystagmus, initial hypotonia progressing to spastic paraplegia, ataxia, tremors, dystonia and other abnormal movements of the limbs, white matter dysmyelination, and basal ganglia deposits – do not appear to be related to the size of the duplications.

Duplication of HUWE1

Sequence variants in HUWE1 have been associated with Juberg-Marsidi syndrome, Brooks syndrome, Turner XLID-macrocephaly syndrome, and a family in which males had moderate ID and normal facial appearance (Friez et al 2016; Turner et al. 1994; Froyen et al. 2008). Duplication of HUWE1, usually associated with a HSD17B10 duplication, has been associated with ID of moderate severity, limited speech or dysarthria, facial dysmorphism (hypertelorism, upslanted palpebral fissures, synophrys, open mouth) and usually normal prenatal and postnatal growth measurements (Froyen et al 2008; Whibley et al. 2010; Orivoli et al. 2016). Two families (IDX17 and IDX31) had no distinctive dysmorphism and had normal growth. Seizures occurred in several patients, one individual had submucous cleft palate and two boys had first-degree hypospadias.

Duplication of STAG2

A number of duplications of Xq25, a gene poor region have been reported in males and females. STAG2, which encodes a subunit of the cohesin complex, is completely duplicated in these cases and adjacent genes (XIAP, THOC2, GRIA3, SH2D1A, and TENM1) are variably duplicated completely or partially (Kumar et al. 2015). The phenotype is dominated by ID of variable severity. Other common features include normal stature and head circumference, malar flatness, thick lip vermilion, prognathism, facial hypotonia and behavioral problems. Seizures and autism occur in a third or less. In contrast, individuals with deletions or sequencing variants of STAG2 have more severe developmental failure, growth impairment, microcephaly and midline malformations including holoprosencephaly or other CNS anomalies, facial clefting, and ocular colobomas.

Duplication of MECP2

Rett syndrome, due to deletions or sequence variants in MECP2 and characterized by a period of normal development in infancy followed by microcephaly and episodic but unrelenting course of neurological deterioration, loss of purposeful hand use, seizures, and spasticity, differs quite substantially from the manifestations of patients with MECP2 duplications. From birth, patients with duplications have hypotonia which later in childhood progresses to spasticity, absent or limited speech and ambulation, and recurrent respiratory infections which often requires tracheostomy and ventilator care. They have severe ID often complicated by seizures, and most die prior to age 25 years (Meins et al. 2005; van Esch et al. 2005; Friez et al. 2006, Vignoli et al. 2012; Lim et al. 2017). Although initially described as an X-linked recessive syndrome in males, more recent reports have confirmed occurrence in females, generally expressed as infantile hypotonia progressing to spasticity, severe ID and neurodevelopmental manifestations including autism spectrum disorder (Scott Schwoerer et al. 2014; Fieremans et al. 2014).

Duplication of OCRL

Lowe syndrome, caused by sequence variants or deletions of OCRL, is characterized by early onset cataracts, depressed muscle tone and reflexes, aminoaciduria, and ID. Duplication of OCRL has been described in 3 families, all in the company of duplications of adjacent genes (Møller et al. 2014; Schroer et al. 2012). They have had neurodevelopmental abnormalities, ID, autism, and seizures but in no other respect has the phenotype of Lowe syndrome been seen among these boys.

Concluding Remarks

In spite of the progress made over the past 30 years, much remains to be done before the XLID field may be considered fully defined. Perhaps as many as 80 additional genes could still be implicated in XLID. Discovery of pathogenic mechanisms probably represents the next biggest challenge, requiring intense efforts by several laboratories and proportionately large financial support. Is this justifiable? The question is legitimate, in view of the rarity of each individual condition, with the exception of the fragile X syndrome and a small number of other XLID syndromes, and of the limited resources available. On the other hand, if the effort conducted so far were meant to be, as in fact it is, preparatory to the ultimate goal, namely the cure, or at least the improvement, of XLID, it would not make sense to halt studies now. The current state of XLID knowledge has little to offer to further such an ultimate goal. As for most genetic diseases, few are the therapeutic successes. Enzyme infusions, stem cell and bone marrow transplantation, drugs and dietary management have been partially effective in a small number of conditions, e.g. ornithine transcarbamoylase deficiency, Hunter syndrome, adrenoleukodystrophy and phosphoglycerate kinase deficiency. A more widely applicable intervention, gene therapy, is on the horizon, with the recent development of delivery vectors that appear to reach target tissues and avoid safety concerns of the past (Hocquemuller et al. 2016), but at the present time it continues to be a hope for the future.

In the meanwhile, a number of outstanding issues continue to challenge clinicians, scientists and families alike. Clinicians must consider in the differential diagnosis a large number of syndromes when evaluating a male with ID and somatic, neurologic, or behavior manifestations and an almost equally large number of possibilities when evaluating a male with ID and no other manifestations. Family history does not help in isolated cases, but can be very informative in kindreds with multiple affected individuals. Physical examination continues to be the basic tool of clinical diagnosis, now aided by a number of genetic databases, including OMIM, POSSUM and Face2Gene. Recognition and use of the human phenotype ontology will bring consistency in describing the clinical manifestations of the various XLID disorders (Robinson et al. 2008).

For scientists, the unresolved issues are no less daunting. While acknowledging the disproportionate progress of identifying ID-associated alterations on the X-chromosome in comparison to ID-associated alterations on the autosomes, knowledge about the impact of these alterations on cellular organization and functions remains limited (Vissers et al. 2010, Dekker and Mirny 2016, Kochinke et al. 2016, Schwarzer et al. 2017). Although sequence variants of uncertain pathogenicity continue to distress laboratory and clinical geneticists, a more systematic approach to their resolution with functional studies including protein modeling, enzyme analysis, metabolomics, RNAseq, immunofluorescence studies of the protein in cell cultures and animal models is being formulated in many laboratories. Recently emerged technologies promise to identify alterations of the X-chromosome, especially involving the noncoding regions of the genome, for those XLID entities which have not been resolved with currently used technologies. These include whole genome sequencing, higher resolution microarray analysis, and structural rearrangement detection (Bionano Genomics).

As to the families, the main services which can be offered continue to be estimation of recurrence risks, preimplantation and prenatal diagnosis, ultrasonographic monitoring of at risk pregnancies, best possible neonatal treatment in cases requiring intensive care, habilitation therapies and advocacy for their needs. The development of treatments which significantly ameliorate the signs and symptoms of the XLID disorders has been disappointingly slow and current clinical trials have limited outcome goals. Abandonment of the notion that the brain is not accessible and development of methods to produce adequate amounts of native genes or CRISPR-cas engineered genes are only two of the major hurdles that gene therapy must overcome before reaching the bedside of patients with XLID disorders (Hocquemiller et al. 2016).

Most X-linked disorders are rare and thus access to multiple cases will be limited. Utilization of GeneMatcher to locate other cases with variants in XLID genes helps to connect researchers and clinicians which stimulate the pursuit of functional studies. In the end, it should not be forgotten that the alliance between physicians, scientists and families has spawned some of the greatest successes in discovering the causes of genetic diseases and delineating their phenotypes.

Supplementary Material

Supp TableS1

Footnotes

Conflicts of Interest: All authors declare that there are no conflicts of interest.

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