FG Syndrome: Report of Three New Families WithLinkage to Xq12-q22.1

John M. Graham, Jr.,1 Darci Tackels,2,3 Kurt Dibbern,1 Duane Superneau,4 Curtis Rogers,3Ken Corning,3 and Charles E. Schwartz2,3*1Medical Genetics Birth Defects Center, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric ResearchCenter, SHARE’s Child Disability Center, UCLA University Affiliated Program, International Skeletal DysplasiaRegistry, UCLA School of Medicine, Cedars-Sinai Medical Center, Los Angeles, California

2Center for Molecular Studies, J.C. Self Research Institute, Greenwood, South Carolina3Greenwood Genetic Center, Greenwood, South Carolina4Ochsner Medical Institutions, New Orleans, Louisiana

FG syndrome is a rare X-linked recessiveform of mental retardation, first describedby Opitz and Kaveggia in 1974 in five relatedmales with mental retardation, dispropor-tionately large heads, imperforate anus, andcongenital hypotonia. Partial agenesis ofthe corpus callosum was noted in at leastone of the initial cases and has been seen ina number of subsequently-reported cases.The associated congenital hypotonia withjoint hyperlaxity tends to progress to con-tractures with spasticity and unsteady gaitin later life. The presence of subtle facial ab-normalities and the characteristic behaviorin midchildhood facilitate diagnosis at thisage, particularly when there are other af-fected male relatives in the maternal family.Recently, Briault et al. [1997] mapped a genefor FG syndrome to the Xq12-q21.31 region.We describe three additional families (sixadditional patients) with FG syndrome onwhom we have conducted linkage analysis.Our findings support the localization of agene for the FG syndrome in Xq12-q21. Inaddition, we have noted skewed X-inactiva-tion in carrier females, as well as new asso-ciated findings in affected males of sagittalcraniosynostosis and split hand malforma-tion. Am. J. Med. Genet. 80:145–156, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: X-linked mental retardation;congenital hypotonia; macro-

cephaly; constipation; agen-esis of the corpus callosum;FG syndrome

INTRODUCTION

FG syndrome is an X-linked form of mental retarda-tion associated with complete or partial agenesis of thecorpus callosum; minor facial anomalies (high, broadforehead with frontal cowlick; ocular hypertelorism;lateral displacement of medial canthi; down-slantedpalpebral fissures; prominent lower lip; high-archedpalate; and abnormal auricles); relative macrocephaly;broad thumbs and hallices; prominent fetal fingerpads; failure to thrive; and characteristic friendly, lo-quacious, hyperactive behavior with occasional aggres-sive outbursts. Since first described by Opitz and Ka-veggia in 1974, over 50 cases have been reported. Af-fected individuals typically suffer from neonatalhypotonia and severe constipation, with or withoutanal anomalies. The constipation usually resolves dur-ing midchildhood, and the congenital hypotonia withjoint hyperlaxity tends to evolve into spasticity withjoint contractures and unsteady gait in later life [Ro-mano et al., 1994]. Death due to pulmonary complica-tions may occur during infancy, with long-term sur-vival noted in the remaining cases (Thompson andBaraitser, 1987; Sorge et al., 1996). We report clinicalfindings in five boys and one man from three new fami-lies, with linkage to Xq12-q21 and skewed X-inactivation in some carrier females.

CLINICAL REPORTS

Three unrelated families with FG syndrome wereseen at Cedar-Sinai Medical Center (family 8610),Ochsner Medical Institutions (family 8890), and theGreenwood Genetic Center (family 8675). Pedigreesare presented in Figure 1. Family 8610 has two af-fected males in two generations. A third male died at

Contract grant sponsor: NICHD; Contract grant number:HD26202, Contract grant sponsor: South Carolina Department ofDisabilities and Special Needs.

*Correspondence to: Charles E. Schwartz, Ph.D., J.C. SelfResearch Institute of Human Genetics, Greenwood GeneticCenter, 1 Gregor Mendel Circle, Greenwood, SC 29646. E-mail:schwartz@ggc.org

Received 4 April 1998; Accepted 22 June 1998

American Journal of Medical Genetics 80:145–156 (1998)

© 1998 Wiley-Liss, Inc.

age 4 days with a congenital heart defect. In family8890 there are two affected sibs. Family 8675 also hastwo affected males in two generations. A third maledied at age 3 weeks with a congenital heart defect andimperforate anus.

IV-3 (Family 8610)

The propositus was born at term with Apgar scores of4, 6, and 6 at 1, 5, and 10 minutes due to poor respira-tory effort and congenital hypotonia. Birth weight was

Fig. 1. Pedigrees of three families (A: Family K8610; B: Family K8890; C: Family K8675) with FG syndrome. Haplotype data for X chromosome lociis given below all persons studied. Boxed haplotype is the presumed ‘‘at risk’’ haplotype. Black square , affected male; boxed number, X-inactivation statusof female.

146 Graham et al.

3540 g (50–75th centile), length 53.5 cm (90th centile),and head circumference (OFC) 35.5 cm (50–75th cen-tile). He had turricephaly; small, apparently low-set,cupped, posteriorly angulated ears; hypertelorism withdown-slanted palpebral fissures; microstomia withhigh-arched palate; inguinal testes; lack of rightmiddle digital ray with 4-5 syndactyly; left singletransverse palmar crease; broad thumbs; and duplica-tion of the right great toe (Fig. 2). Imaging studies dem-onstrated hypoplasia of the corpus callosum.

He had a maternal uncle with severe mental retar-dation and absent corpus callosum (III-4, Fig. 1). An-other uncle died at 4 days with a congenital heart de-fect (III-1, Fig.1). The propositus’s mother had repairedduodenal stenosis as a newborn infant neonate, with nominor anomalies. The propositus was treated for apneaand feeding difficulties which resolved, and he wasgiven a partial exchange transfusion for polycythemiawith hematocrit of 69%. He was discharged on an ap-nea monitor at 8 days with persistent hypotonia, de-creased brainstem auditory evoked responses, pulmo-nary hypertension with right ventricular hypertrophyby echocardiogram (attributed to upper airway ob-struction), normal pneumogram, normal renal ultra-sound findings, normal chromosome, and normal elec-troencephalogram (EEG). Cranial computed tomogra-

phy (CT) at 3 days showed a small cavum septumpellucidum, and cranial magnetic resonance imaging(MRI) at 2 years demonstrated hypoplasia of the pos-terior corpus callosum with mild ventricular dilatationand mild frontal atrophy.

At 2 3/12 years, his length, weight, and OFC were allat the 50th centile; he had experienced one febrile sei-zure; his pulmonary hypertension had resolved byechocardiogram; and his tone was only mildly de-creased. At 2 7/12 years, the propositus was prescribedphenobarbital and carbamazepine for twitching move-ments of his shoulders that occurred several times perday. He had become hyperactive with aggressive out-bursts, so the phenobarbital was discontinued, and di-phenylhydantoin therapy was initiated. An EEG at 2years 10 months was abnormal due to recurrent rightcentral spike and sharp waves with a few left temporalsharp waves. Seizures remained poorly controlled, sohe was treated instead with valproic acid. At age 5years he had a developmental quotient of 50 and re-quired special education classes. He had a friendly dis-position, hyperactive behavior, and a history of consti-pation. He was taking valproic acid, carbamazepineand methylphenidate. His height was at the 10th cen-tile, with weight at the 50th and OFC at the 25th centile.

Fig. 2. Patient 1 (VI-3, K8610); note minor anomalies (A–C), duplication of the right great toe (D) and right 4-5 syndactyly (E).

FG Syndrome Linked to Xq12-q21.31 147

III-4 (Family 8610)

Our second patient is the 34-year-old maternal uncleof Patient 1. He has been institutionalized since age 2years. He was born at term to an 18-year primigravidawoman and her 22-year-old husband after an unevent-ful pregnancy. His birth weight was 3400 g (50th cen-tile). A right inguinal hernia was repaired at age 6weeks, and he had a history of left inguinal testis withbilateral kidney stones and intermittent mild left hy-dronephrosis. He was profoundly retarded with an IQof 5 at 15 years of age and a long history of self-abusivebehavior resulting in facial trauma, left phthisis bulbi,and right cataract resulting in blindness. He had a his-tory of neonatal hypotonia with hydrocephalus andagenesis of the corpus callosum demonstrated by pneu-moencephalogram. He had stenotic ear canals but nor-mal hearing. Other studies included a normal electro-cardiogram and normal electroencephalogram (EEG).A CT scan at age 32 years showed dolichochephaly,mild hydrocephalus, and a prominent cisterna magna.His chronic constipation was managed with supposito-ries, and he had incontinence of bladder and bowel.

At 34 years, his height was 162 cm (<3rd centile),weight 47.5 kg (<3rd centile), and OFC 59.5 cm (>95thcentile, +3 SD). Physical findings include: dolichoce-phalic head shape with posterior sagittal ridging sug-gestive of sagittal synostosis; high prominent forehead;

ear anomalies; broad thumbs and hallices; camptodac-tyly; broad fingertips; bilateral single transverse pal-mar creases; partial cutaneous syndactyly of all fingerson the right; partial 2-3 and 4-5 cutaneous finger syn-dactyly on the left; pectus excavatum; left inguinal tes-tis; and an anteriorly placed anus (Fig. 3). He also hada dislocated left hip, joint contractures, and bilaterallower limb spastic paraparesis. Dermatoglyphics of fin-gers included 4 arches, 2 radial loops, and 4 ulnarloops.

II-1 (Family 8890)

Patient 3 was born at 38 weeks of gestation to a25-year-old primigravida woman with an unremark-able family history. At birth he weighed 3458 g (75thcentile), was 49 cm long (25th centile), and had an OFCof 35.5 cm (75th centile). He was born with hypotonia,respiratory distress, and feeding problems due to apoor suck. An initial EEG was normal, and CT scan at5 months suggested prominent extracerebral fluid withpartial agenesis of the corpus callosum. The CT scanwas confirmed by MRI at 9 months, and follow-up MRIat 27 months demonstrated persistent extracerebralfluid collections, suggesting cortical atrophy, withmarked hypoplasia of the corpus callosum and poordefinition of the fornix and septum pellucidum.

He had difficulties with chronic constipation treated

Fig. 3. Patient 2 (III-4, K8610); note ear abnormalities (A–B), dolichocephaly (C), broad hallices (D), and anteriorly placed anus (E).

148 Graham et al.

by suppositories and diet, and this had improved by age4 years, when tympanostomy tubes were inserted forchronic otitis media. He developed progressive contrac-tures of hips, knees, and ankles, requiring bilateraltendon lengthenings around these joints, and wastreated with amitryptyline for defective superficial pe-roneal nerve conduction. At 5 10/12 years, he had se-vere mental retardation, with disproportionately im-paired expressive language, and receptive languagecommensurate with his cognitive abilities. Chromo-somes were normal, including fluorescent in situ hy-bridization (FISH) for deletion of the Angleman syn-drome region, and results of molecular analysis forfragile X syndrome were normal.

At age 7 11/12 years, height and weight were at the25th centile, and OFC at the 97th centile. He had doli-chocephaly with a frontal upsweep; right frontal hairwhorl; upslanted palpebral fissures; ocular hypertelor-ism; posteriorly angulated auricles with posterior au-ricular dimples; full lips; maxillary overbite withnotched upper central incisors; wide alveolar ridges;midpalatal ridging; pectus excavatum; diastasis recti;broad thumbs and great toes; prominent fetal pads onhis digital tips; normal palmar creases; normal genita-lia and anus; and slight hyperreflexia (Fig. 4). Derma-toglyphics showed nine whorls and one double loop,with a missing C triradius and a lateral shift of the Atriradius on the right palm. He was nonverbal, withsome receptive understanding and a better attentionspan than his brother. He had occasional temper tan-trums with biting and pinching, enjoyed music, andwas able to express affection.

II-2 (Family 8890)

Patient 4 was the younger brother of Patient 3. Hewas born at term despite onset of early labor treatedwith bedrest. He was born weighing 3600 g (50–75thcentile). Postnatally, he was hypotonic with decreasedactivity, and he required surgery for pyloric stenosis.Postoperatively, he manifested failure to thrive, devel-opmental delay, and chronic constipation treated withenemas, laxatives, and diet. A cranial CT scan was nor-mal at 4 months. He crawled at 8 months, took steps at18 months, and had numerous falls, resulting in a hair-line skull fracture at age 2 years. He also had flu-likeillnesses resulting in dehydration during infancy.

With time, he became hyperactive with a short at-tention span. On examination at 27 months, his ap-pearance was similar to that of his older brother, withheight and weight at the 25th centile, and OFC at the97th centile. He had dolichocephaly with a frontal up-sweep; upslanting palpebral fissures; prominent upperalveolar ridges; accentuated folding around the anti-tragus with posterior angulation of the ears; pectusexcavatum; no cardiac murmur; diastasis recti; normalgenitalia and anus; left Sydney crease; mildly broad-ened thumbs and great toes; and persistence of fetalfingertip pads (Fig. 5). On the fingertips he had twoulnar loops and three whorls on the left hand (righthand not recorded), with missing C triradii. At 32months, social skills were at 17 months, with severe-profound delays in communicative skills, and mild-

moderate delays in cognitive skills, fine motor skills,and gross motor skills.

The mother had five whorls, four ulnar loops, andone radial loop with a missing C triradius on the rightand lateral displacement of the C triradius on the left.She had a scar on the left fifth finger from removal of apolydactylous digit, a bicornate uterus, and mitralvalve prolapse. Paternal dermatoglyphics showed 10ulnar loops and normal triradii.

II-5 (Family 8675)

Patient 5 was the product of a term vertex vaginaldelivery, born to a 36-year-old G4P3Ab1 woman with anegative family history for other males with mentalretardation. A previous brother had been born with animperforate anus and died at age 3 weeks with a con-genital heart defect (ventricular septal defect) (II-1,Fig. 1). His birth weight was 3665 g (75th centile) withlength 53.5 cm (90th centile), and OFC 34 cm (25thcentile). At birth he had congenital hypotonia, mem-branous imperforate anus, and small, posteriorly an-gulated cup-shaped ears. An echocardiogram on thepropositus was normal, and he developed tracheoma-lacia with a pectus excavatum. At 6 months he wasseen by a neurologist who noted developmental delay,generalized hypotonia, alternating exotropia that in-creased with downward gaze, and abnormally placedthumbs. He did not have seizures, and his OFC was atthe 50th centile. At 11 months an ophthalmologistnoted mild optic atrophy with subnormal visual acuity.Cranial imaging at 40 months demonstrated partialagenesis of the corpus callosum. During adenoidectomysurgery, a vocal cord cyst was found and removed.

Developmental assessment at 15 months demon-strated a developmental quotient of 50 on the BayleyScales of Infant Development. On the Vineland Scaleshis communicative skills were at 10 months, daily liv-ing skills at 11 months, socialization skills at 12months, and motor skills at 8 months. His performanceat this age suggested that he was mildly to moderatelyretarded. At age 18 months initial genetic evaluationdocumented mildly broad thumbs and hallices, promi-nent forehead, mild ocular hypertelorism with bilateralepicanthal folds, and persistent hypotonia, suggestingthe diagnosis of FG syndrome. Chromosomes were nor-mal. The patient returned for follow-up at age 4 years.Facial anomalies were unchanged, the sagittal suturewas ridged, and he had a narrow palate (Fig. 6). He haddeveloped a friendly, loquacious personality, but hadoccasional temper tantrums with persistent develop-mental delay.

III-1 (Family 8675)

Patient 6 is the nephew of Patient 5. He was bornsmall for gestational age with respiratory distress,small ventricular septal defect (VSD), and membra-nous imperforate anus. His birth weight was 1335 g(10th–25th centile). He had a prominent forehead withpartial absence of the corpus callosum, upswept frontalhair pattern, downslanted palpebral fissures, smallcup-shaped ears, mildly broad thumbs and hallices,and bilateral inguinal hernias that required surgical

FG Syndrome Linked to Xq12-q21.31 149

Fig. 4. Patient 3 (II-1, K8890); note dolichocephaly and facial appearance (A,B), posteriorly angulated ears (C), and broad thumbs (D) and hallices(E).

150 Graham et al.

Fig. 5. Patient 4 (II-2, K8890); note dolichocephaly anomalies (A,B), the posteriorly angulated ears (C), and mildly broadened thumbs (D) and hallices(E).

correction. He did not have hypotonia. At 2 months,when discharged from his initial hospitalization, heweighed 3300 g (<3rd centile), measured 50 cm inlength (<3rd centile), and had a OFC of 35.2 cm (<3rdcentile). He was hospitalized for pneumonia at 8months, and by 11 months he was found to have severemyopia with moderate developmental delay. He devel-oped seizures at age 32 months and was treated withclonazepam. CT scan documented partial agenesis ofthe corpus callosum. At 51⁄2 years he had an OFC of 52cm (60th centile), broad thumbs, and facial anomaliessimilar to those of his uncle (Fig. 7). The dermatoglyph-

ics showed 3 whorls and 2 ulnar loops on the right handand 2 whorls and 3 ulnar loops on the left hand.

METHODS

Genomic DNA was isolated from circulating lympho-cytes using a high salt precipitation procedure[Schwartz et al., 1990]. Specific microsatellite polymor-phisms were generated according to either Nelson et al.[1995] or Dib et al. [1996]. Forward primers were syn-thesized and labeled with fluorescein amidite (FluoreP-rime, Pharmacia) using a Beckman 1000 DNA synthe-sizer. Primers were desalted using Sephadex G-25 col-

Fig. 6. Patient 5 (II-5, K8675); note the anomalies (A,B) and the broad thumbs (C) and hallices (D).

152 Graham et al.

umns (NAP-10, Pharmacia, Piscataway, NJ). Allpolymorphisms were detected on an Automated LaserFluorescent Sequencer (ALF, Pharmacia) using theAutomated Linkage Preprocessor (ALP) software[Mansfield et al., 1994]. Two-point linkage analysiswas conducted using Fastlink, version 3.0 [Cottinghamet al., 1993]. The gene frequency was set at 0.0001 withfull penetrance in males. X-inactivation status was as-sessed by examining methylation at the AR (androgenreceptor) locus on Xq12 as previously described byPlenge et al. [1997].

RESULTS

Based on previous linkage analysis in a single FGfamily [Zhu et al., 1991], markers located in the proxi-mal long arm of the X chromosome were employed foranalysis. A maximum lod score of 1.93 at u40.00 wasobtained at loci DXS986 (Xq21.1) and DXS101 (Xq22.1)(Table I). Recombination was observed at AR (Xq12) in

Family 8610 and at DXS1072 (Xq22.3) in Families8675 and 8890. Haplotype analysis confirmed thesefindings (Fig. 1). However, as individual II-2 in Family8675 is homozygous at DXS1210, it is possible the dis-tal recombination occurred between DXS101 andDXS1210 rather than between DXS1210 andDXS1072.

Linkage to hypoxanthine phosphoribosyltransferase(HPRT) in Xq26 was excluded in Family 8610. This issignificant because of the 4-5 syndactyly in Patient 1and the localization of a gene for split hand/split foot(SHFM2) in Xq26 [Faiyaz ul Haque et al., 1993]. Fur-thermore, linkage to markers in Xq28 was excluded forall three families, thus ruling out this region as beinginvolved. A gene for FG may be located in Xq28, basedon the observation of an inv (X)(q11q28) segregatingwith a FG syndrome presentation in a single family[Briault et al., 1996].

Relative expression of alleles at the androgen recep-

Fig. 7. Patient 6 (III-1, K8675); note the anomalies (A,B) similar to those of his uncle (II-5) and the mildly broad thumbs (C) and hallices (D).

FG Syndrome Linked to Xq12-q21.31 153

tor (AR) locus was determined using methylation sta-tus. Female carriers in Families 8675 and 8890 exhib-ited complete skewing of X-inactivation (Fig. 1). How-ever, the difference in X-inactivation between carrierand noncarrier was not as clear in Family 8610. InFamily 8610, two noncarriers had relative ratios of 54:46

(III-3) and 62:38 (IV-1), while the two carriers who weretested had ratios of 80:20 (I-2) and 73:27 (II-2) (Fig.1).

DISCUSSIONFG syndrome is a rare X-linked recessive form of

mental retardation, first described by Opitz and Ka-

TABLE I. Two Point Lod Scores for Various X Chromosome Loci vs. FG Syndrome in Three Families

154 Graham et al.

veggia in 1974 in five related males with mental retar-dation, disproportionately large heads, imperforateanus, and congenital hypotonia. Partial agenesis of thecorpus callosum was noted in at least one of the initialcases. With the availability of cranial MRI scans inrecent years, partial agenesis of the corpus callosumhas been seen in a number of recently reported cases[Richieri-Costa, 1986; Opitz et al.,1988; Kato et al.,1994; and Sorge et al., 1996]. Opitz et al. [1982] sug-gested that the diagnosis of FG syndrome must be con-sidered in boys with congenital hypotonia and anorec-tal anomalies, and in older males with mental retarda-tion, congenital hypotonic joint contractures, chronicconstipation, and characteristic facial appearance andpersonality. The presence of complete or partial agen-esis of the corpus callosum makes this diagnosis evenmore compelling.

Follow-up reports of families initially reported byOpitz and Kaveggia [1974], Keller et al. [1976], Ric-cardi et al. [1977], Burn and Martin (1983), andThompson et al. (1985) are included in reports by Opitzet al. [1982], Thompson et al. [1986], and Romano et al.[1994], including neuropathology from several of theinitial cases. Neuropathology findings include megalo-encephaly, midline fusion of mamillary bodies, andneuroglial heterotopias with cerebral cortical dysgen-esis and pachygyria suggesting a diffuse defect of neu-ronal cell migration [Opitz et al., 1982; and Thompsonet al., 1986].

The associated congenital hypotonia with joint hy-perlaxity usually progresses to contractures with spas-ticity and unsteady gait in later life [Romano et al.,1994]. Lethality during infancy has been reported in asmany as a third of patients, as a consequence of bron-chopulmonary problems and/or heart defects, but oncepatients have survived infancy, death is rare [Opitz etal., 1982; Thompson and Baraitser, 1987; and Sorge etal., 1996]. The presence of minor anomalies (macro-cephaly, broad forehead with frontal upsweep, andbroad thumbs and toes with persistent fetal pads) andcharacteristic behaviors facilitate diagnosis in mid-childhood, particularly when there are other affectedmale relatives in the maternal family.

Hyperactive behavior, affability, excessive talkative-ness, and epilepsy have been described in some pa-tients [Thompson and Baraitser, 1987; Opitz et al.,1988; Romano et al., 1994]. The ears in FG syndromeare usually low-set, small, rounded, and cupped with aslightly over-folded superior helix and posterior angu-lation. With the high, broad forehead and dolichoce-phalic head shape, the smallness of the ears may ap-pear accentuated. Constipation, with or without analanomalies, is a distinctive major finding of FG syn-drome. It may not resolve until middle childhood formany patients [Romano et al., 1994]. Mental retarda-tion is a universal finding, and sensorineural hearingloss has been reported in several cases [Neri et al.,1984; Romano et al., 1994]. Other nonspecific occa-sional anomalies include abnormal pinnae, hypertelor-ism, pyloric stenosis, cryptorchidism, hypospadia, her-nia, single transverse palmar creases, syndactyly, andcamptodactyly [Opitz et al., 1988]. To these rare mani-festations we add sagittal craniosynostosis and ecto-

dactyly. Congenital hypotonia secondary to CNS in-volvement also appears to be a very important distin-guishing manifestation in this syndrome. Hypotoniaappears to result in many of the characteristic findingsin FG syndrome including early respiratory distress,arched palate, typical facies, sloping shoulders with a‘‘slouched’’ posture, pectus deformities, kyphoscoliosis,herniae, cryptorchidism, and pes planus [Opitz et al1988]. Poor tone also likely contributes to (but may notfully explain) the severe constipation affecting theseindividuals. Early hypotonia also frequently evolvesinto joint contractures later in life, and maternal car-riers may manifest constipation, broad forehead withor without frontal cowlick, macrocephaly, ocular hyper-telorism, and/or congenital hypotonia [Romano et al.,1994].

Linkage analysis in three families with FG syndromeresulted in a broad localization ranging from the ARlocus in Xq12 to the DXS1210 locus in Xq23 (Table I). Amaximum two-point lod score of 1.93 was observed inthis interval at DXS986 and DXS101. This finding isconsistent with those recently reported by Briault et al.[1997]. The distance between AR and DXS1072 is onthe order of 45 Mb [Nelson et al., 1995], considerablylarger than the region defined by Briault et al. [1997].However, as those authors pointed out, using a molecu-lar analysis of two males with deletions of Xq21 and nosigns of the FG syndrome [May et al., 1995], it is pos-sible to exclude the region distal to DXS72. Doing soreduces the area of localization to the AR-DXS72 re-gion or 18 Mb [Nelson et al., 1995].

Within this region there is one good candidate gene,XNP (X-linked nuclear protein). Mutations in this genecause the ATR-X syndrome (X-linked alpha-thalassemia, mental retardation) [Gibbons et al., 1995;Villard et al., 1997]. ATR-X patients have severe men-tal retardation (MR), congenital hypotonia, character-istic facies, genital abnormalities, and a small headcircumference [Gibbons et al., 1991]. FG patients havemoderate MR, hypotonia, characteristic facies, andconstipation with or without anal anomalies [Thomp-son and Baraitser, 1987]. However, patients with FGsyndrome differ from patients with ATR-X in that theyhave macrocephaly, partial agenesis of the corpus cal-losum, and a friendly personality with hyperactive be-havior. Another point of interest is the observation thatcarrier females in ATR-X families have almost com-pletely skewed X-inactivation [Gibbons et al., 1995].Carrier females in Families 8675 and 8890 exhibitedthis, while the X-inactivation observed in females inFamily 8610 was only suggestive of skewing. As a re-sult, further consideration of XNP as a candidate genefor FG in the families reported herein seems war-ranted.

Lastly, it should be noted that the haplotype analysisin Family 8610 clearly indicates that II-1 is a new mu-tation and that the mutation arose on her paternal Xchromosome (Fig. 1). This is of considerable interest, asit would appear that many X-linked conditions are dueto new mutations on the paternal X-chromosome[Thomas, 1996].

FG Syndrome Linked to Xq12-q21.31 155

ACKNOWLEDGMENTS

We wish to thank members of the three families fortheir cooperation. Millie Justice prepared the manu-script.

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