Velocardiofacial Syndrome

A number sign (#) is used with this entry because the velocardiofacial syndrome and DiGeorge syndrome (DGS; 188400) are caused by a 1.5- to 3.0-Mb hemizygous deletion of chromosome 22q11.2. Haploinsufficiency of the TBX1 gene (602054) in particular is responsible for most of the physical malformations. There is evidence that point mutations in the TBX1 gene can also cause the disorder.

Clinical Features

The del22q11 syndrome is associated with a highly variable phenotype despite the uniformity of the chromosomal deletion that causes the syndrome in most patients.

Shprintzen et al. (1981) reported on 39 patients with a syndrome characterized by the following frequent features: cleft palate, cardiac anomalies, typical facies, and learning disabilities. Less frequent features included microcephaly, mental retardation, short stature, slender hands and digits, minor auricular anomalies, and inguinal hernia. The Pierre Robin syndrome was present in 4. The heart malformation was most often ventricular septal defect. In the group studied, mother and daughter were affected in 2 instances, mother and son in 1, and mother and both daughter and son in 1.

Fitch (1983) found small optic discs with tortuous vessels in an affected 6-year-old girl, the offspring of first-cousin parents.

Wraith et al. (1985) reported a male infant with holoprosencephaly and tetralogy of Fallot with death at 32 days. The mother had the same heart lesion, tetralogy of Fallot (totally corrected by surgery at age 12 years), and a large submucous cleft palate causing nasal voice. Her face was considered typical of VCF syndrome: prominent tubular nose, narrow palpebral fissures, and slightly retruded mandible. She was mildly retarded. Another child, female, may have been affected. The authors suggested that the association of tetralogy of Fallot and prosencephaly should prompt search for signs of VCF syndrome in relatives.

Shprintzen et al. (1985) claimed that VCFS is the most frequent clefting syndrome, accounting for 8.1% of children with palatal clefts seen in their center. Learning disabilities characterized by difficulty with abstraction, reading comprehension, and mathematics is found in all cases as is a characteristic facial dysmorphia. Cardiac anomalies were found in 82%. Platybasia occurred in 85%. Ophthalmologic abnormalities, including tortuous retinal vessels, small optic discs, posterior embryotoxon, or bilateral cataracts, were observed in 70%. Neonatal hypocalcemia requiring treatment occurred in almost 13%. Small or absent lymphoid tissue was documented by nasopharyngoscopic examination in a great majority. Most patients had frequent infections, and T-lymphocyte dysfunction was found. Male-to-male transmission established autosomal dominant inheritance.

Marked tortuosity of the retinal vessels, as noted in earlier reports, was commented on by Beemer et al. (1986).

Meinecke et al. (1986) reported 8 patients with the VCF syndrome; 3 cases were sporadic and 5 others occurred in 2 families. The authors concluded that the frequency of cardiovascular anomalies and cleft palate has been incorrectly estimated to be high, 98% and 82%, respectively, because patients have been ascertained in cardiac or cleft palate clinics. Their 8 patients were diagnosed mainly through their pattern of facial dysmorphism and only 2 and 4 of the 8, respectively, had clefts and heart defects. Furthermore, mental retardation, noted in all cases in previous publications, was not present in any of these 8 patients. They suspected that the rate of fresh mutations may not be as high as previously assumed because of mild expression in some family members.

Williams et al. (1987) found evidence for congenital hypoplasia of the adenoids in over four-fifths of patients with the VCF syndrome. They suggested that this feature contributes to the hypernasal speech found in persons with this condition because normally velopharyngeal closure during speech is aided by the adenoids.

Lipson et al. (1991) reported on 38 cases including 2 familial cases. They emphasized the frequent delay in diagnosis and treatment for the hypernasal speech and velopharyngeal insufficiency. Overt cleft palate was present in 7 of the cases and submucous cleft in 15. Congenital heart disease was present in 16. Velopharyngeal insufficiency was present in all but one; pharyngoplasty was performed in all but 6 of the cases and results were good in all of these. Lipson et al. (1991) published photographs illustrating the main facial features: almond-shaped palpebral fissures, deficient nasal alae, bulbous nasal tip in older children, myopathic facies, and small open mouth. Hypernasal speech was often the finding that brought the children to attention.

Goldberg et al. (1993) reviewed the full spectrum of the velocardiofacial syndrome on the basis of 120 patients. Learning disability, cleft palate, and pharyngeal hypotonia were present in 90% or more of the patients; cardiac anomalies in 82%; slender hands and digits in 63%; medial displacement of internal carotid arteries in 25%; umbilical hernia in 23%; and hypospadias in 10% of males.

Nickel et al. (1994) reported 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of VCFS; both also had bifid uvula. The third child had DiGeorge sequence.

Kousseff (1984) described 3 sibs with a syndrome of sacral meningocele, conotruncal cardiac defects, unilateral renal agenesis (in 1 sib), low-set and posteriorly angulated ears, retrognathia, and short neck with low posterior hairline. Kousseff (1984) suggested autosomal recessive inheritance. Toriello et al. (1985) reported a similar, isolated case and designated the disorder Kousseff syndrome. Forrester et al. (2002) restudied the family reported by Kousseff (1984) and identified a 22q11-q13 deletion in the proband, his deceased brother, and his father. The proband had spina bifida, shunted hydrocephalus, cleft palate, short stature, cognitive impairment, and the typical craniofacial features of velocardiofacial syndrome, including low-set and dysplastic ears, broad base of the nose, narrow alae nasi, and retrognathia. His brother had died at 2 weeks of age with myelomeningocele, hydrocephalus, transposition of the great vessels, and unilateral renal agenesis, and his sister had died at 22 days of age with myelomeningocele, truncus arteriosus, hypocalcemia, and autopsy findings of absent thymus and parathyroid glands, consistent with DiGeorge anomaly.

Maclean et al. (2004) reported 2 patients with Kousseff syndrome, 1 with a 22q11.2 deletion and the other without. The first was a 4-year-old girl with a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum, and moderate developmental delay, who had a normal chromosome 22q11.2 FISH test and did not exhibit the facial phenotype of VCFS. The second patient, a male infant who died at 10 days of age, had a large sacral myelomeningocele, hydrocephalus, Arnold-Chiari malformation, atrial septal defect, conoventricular ventricular septal defect, type B interrupted aortic arch, hypocalcemia, and suspected duodenal stenosis; FISH testing revealed a 22q11.2 microdeletion. Maclean et al. (2004) concluded that Kousseff syndrome is a distinct clinical entity that is genetically heterogeneous.

Lynch et al. (1995) reported the case of a 34-year-old man who presented for neurologic evaluation for cerebellar atrophy of unknown etiology. By history, he had had neonatal hypocalcemia, an atrial septal defect, and a corrected cleft palate. Physical examination showed the characteristic facies of velocardiofacial syndrome, as well as dysmetria and dysdiadochokinesia consistent with cerebellar degeneration. An MRI scan of his head performed by the authors showed vermian and hemispheric cerebellar atrophy, calcification of the basal ganglia, a small brainstem without focal loss of volume, and multiple white matter lucencies on T2-weighted images. The white matter lesions were suggestive of axonal loss, ischemia, or demyelination. Molecular cytogenetic studies showed a deletion of 22q11.2, del(22)(q11.21-q11.23). This case represented the first report of the association of a neurodegenerative disorder with velocardiofacial syndrome or DiGeorge syndrome.

Ryan et al. (1997) reported a European collaborative study of 558 patients with deletions of 22q11. In 204 of the 285 patients for whom parental deletion status was available, neither parent had the deletion. Of the 81 inherited deletions, the sex of the parent with the deletion was known in 79 cases, with 61 maternal and 18 paternal deletions. Growth data were available for 131 of 158 patients whose heights and/or weights were less than the 50th centile; 57 of 158 were below the 3rd centile for either height or weight. Forty-four patients had died, and of the 29 for whom age of death was available, 16 had died within 1 month and 25 within 6 months as a consequence of congenital heart disease. There was 1 death from severe immune deficiency. A total of 107 of 338 cases were developmentally normal, although 37 of these had speech delay. Of 231 patients with abnormal development, 102 had mild delay and 60 had either moderate or severe learning difficulties. Twenty-two of 252 children in the study had behavioral or psychiatric problems, including 2 with episodes of psychosis; 11 of 61 adults had a psychiatric disorder, 4 of whom had had at least 1 episode of psychosis. Cardiac studies were recorded in 545 patients, of whom 409 had significant cardiac pathology, most commonly tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, pulmonary atresia/ventricular septal defect, and truncus arteriosus. A total of 242 of 496 patients had otolaryngeal abnormalities, with 72 having either an overt cleft palate or submucous cleft; 161 patients had velopharyngeal insufficiency without clefting. Of 159 patients in whom data on hearing were available, 52 had abnormal hearing, with data on the type of hearing loss available in only 17, in all of whom this was conductive in type. A total of 49 of 136 patients had renal abnormalities, with absent, dysplastic, or multicystic kidneys in 23, obstructive abnormalities in 14, and vesicoureteric reflux in 6. A total of 203 of 340 had recorded hypocalcemia; 108 of this group had a history of seizures, and 42 of these had had seizures secondary to hypocalcemia. Most hypocalcemia was reported in the neonatal period, but 1 patient presented at 18 years of age. Laboratory and clinical immune function and thymus status were available in 218 patients. Only 4 of these were classified as having a major immune function abnormality. Two of these had died, with severe immunodeficiency being the cause of death in 1. A total of 94 of 548 patients had minor abnormalities of the skeletal system, and 39 of 548 had ocular anomalies. Ten offspring comparisons showed that 27 of 35 children had more severe congenital heart disease than their parents, with 8 of 35 having the same degree of severity. Developmental status was worse in 9 of 17 and the same in 7 of 17. Palatal abnormalities were better in 10 of 22 children and similar to the parents in 12 of 22 children. Sibship comparisons in 26 sibs from 12 families showed considerable variation in heart abnormalities between sibs, and development status was similar in most cases. Ryan et al. (1997) concluded that most of the clinical findings in their study reflected previous reports; however, fewer immunologic problems and more renal problems than were expected were found. Ryan et al. (1997) therefore recommended that abdominal ultrasound be carried out in all patients with 22q11 deletions. They also recommended that both parents be studied when a child is found to have a deletion.

Vincent et al. (1999) reported the case of female monozygotic twins with 22q11 deletions. The twins shared facial characteristics of DGS/VCFS and immunologic defect. However, only one, who died on day 5, had a cardiac defect, comprised of an interrupted aortic arch with a ventricular septal defect, a truncus arteriosus, and a large arterial duct. The authors stated that this was the fourth report of a discrepant cardiac status between monozygotic twins harboring 22q11 deletions.

Worthington et al. (1997) reported 3 cases of VCFS with anal anomalies (2 cases of anal stenosis and one of a covered anus with a perineal fistula) and confirmed deletions of the 22q11 region by FISH. They presented an additional case of a child with clinical VCFS whose father was born with an imperforate anus and had mental retardation presumably because of VCFS; this family had been lost to follow-up.

Devriendt et al. (1997) reported a female fetus with Potter sequence caused by unilateral renal agenesis and contralateral multicystic renal dysplasia. Additionally, there was agenesis of the uterus and oviducts (Von Mayer-Rokitansky-Kuster anomaly). The father had dysmorphic features typical of VCFS, and fluorescence in situ hybridization analysis confirmed deletions of chromosome 22q11 in both father and fetus. The fetus had no dysmorphic features suggestive of VCFS and no cardiovascular abnormalities.

Sundaram et al. (2007) described 2 patients with 22q11.2 deletion who had absent uterus and unilateral renal agenesis. One patient also had mild developmental delay, hypoparathyroidism, and psychiatric symptoms; the other patient also had high-arched palate, bulbous nasal tip, bicuspid aortic valve, short stature, and primary amenorrhea. Sundaram et al. (2007) suggested that mullerian or uterine/vaginal agenesis be included as part of the clinical spectrum of 22q11.2 deletion syndrome.

Van Geet et al. (1998) studied a family in which all 3 members with a 22q11 microdeletion and VCFS had giant platelets and a mild decrease in platelet number. Platelet function, however, tested by aggregation and by adherence to collagen in a whole blood perfusion system, was normal. They studied the files of 35 other patients with 22q11 deletion and also found that their platelets had an increased size compared with cardiac controls. Moreover, their platelet size correlated negatively with platelet number. Since patients with 22q11 deletion are expected to be heterozygous for deletion of the GP1BB gene (138720), they can be considered to be carriers of the Bernard-Soulier syndrome (231200). A significant increase in platelet size may be a positive predictor for the clinical diagnosis of VCFS.

Digilio et al. (2001) reported on the growth parameters of 73 patients with the 22q11 deletion. In general, these patients were characterized by weight deficiency in the first years of life, weight normalization in the following years, development of obesity in adolescence, short stature in 10% of the patients, normal height in adolescents, slight delay in bone age in infancy, and microcephaly in 10% of the patients.

Jawad et al. (2001) studied 195 patients with chromosome 22q11.2 deletion syndrome and found that diminished T-cell counts in the peripheral blood are common. The pattern of changes seen with aging in normal control patients was also seen in patients with the chromosome 22q11.2 deletion syndrome, although the decline in T cells was blunted. Autoimmune disease was seen in most age groups, although the types of disorders varied according to age. Infections were also common in older patients, although they were seldom life-threatening. Juvenile rheumatoid arthritis with onset between 1.5 and 6 years of age was seen in 4 of the 195 patients; idiopathic thrombocytopenia purpura with onset at 1 to 8 years of age was seen in 8 of 195 patients; autoimmune hemolytic anemia, psoriasis, vitiligo, inflammatory bowel disease, adult rheumatoid arthritis, and rheumatic fever with chorea were each seen in 1 patient of the 195 patients sampled.

Kawame et al. (2001) reported 5 patients with chromosome 22q11.2 deletion that manifested Graves disease between the ages of 27 months and 16 years, and suggested that Graves disease may be part of the clinical spectrum of this disorder.

McElhinney et al. (2001) studied 29 patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age to determine the incidence of cardiovascular anomalies. In 11 of 29 (38%) patients, cardiovascular anomalies were detected, including 3 with a vascular ring, 3 with a right aortic arch with mirror-image branching of the brachiocephalic arteries (no vascular ring; one with a patent ductus arteriosus; see 607411), and 4 with a left aortic arch with an aberrant right subclavian artery (no vascular ring; 1 with a patent ductus), and 1 with a left superior vena cava draining to the coronary sinus. All 3 patients with vascular rings and 1 with a patent ductus arteriosus required intervention, giving an incidence of 14% in this study.

Kessler-Icekson et al. (2002) examined myocardial tissues removed after corrective surgery of 31 patients with congenital heart defects (21 with tetralogy of Fallot and 10 with a double-chamber right ventricle) using a set of 9 polymorphic short tandem repeat markers along the 22q11.2 region. Ten (48%) of the tetralogy of Fallot patients had homozygosity for 3 or more consecutive markers, suggesting possible 22q11.2 deletions. None of the patients with double-chamber right ventricle had this finding.

Martin et al. (2004) identified an altered dermatoglyphic profile in 22q deletion syndrome patients, which involved (1) ATD angle and amplitude, (2) the presence of radial loops in the hypothenar area, and (3) fluctuating asymmetry. Martin et al. (2004) noted that the first 2 features are similar to those found in other genetic syndromes associated with low IQ, whereas high levels of fluctuating asymmetry have often been reported in schizophrenia.

Sandrin-Garcia et al. (2002) described a family in which a patient had the clinical diagnosis of VCFS and his sister had a suggestive phenotype. Both were found to carry a deletion in 22q11.2 of maternal origin. The mother and other unaffected relatives did not show the deletion, suggesting that the mother had gonadal mosaicism with a normal DNA profile in the blood cells.

Conway et al. (2002) described a child with the typical craniofacial manifestations of VCFS and unilateral pulmonary agenesis. They suggested that the patient's pulmonary agenesis was related to a disruption of the dorsal aortic arch development that selectively interfered with lung bud growth and, further, that pulmonary agenesis should be considered part of the spectrum of malformations seen in 22q11.2 deletion. Cunningham et al. (2003) reported a second patient with VCFS, confirmed by genetic detection of 22q11.2 deletion, and unilateral primary pulmonary agenesis. High-resolution CT imaging showed a hypoplastic left lung comprising a single lobe, small left bronchus, hypoplastic left pulmonary artery, and hypoplastic left chest wall with complete shift of the trachea and mediastinum into the left hemithorax. The patient also had congenital conductive hearing loss due to malformation and subluxation of the left stapes, and hypoplasia of the left mandible.

Bassett et al. (2005) described the phenotypic features of 78 adults with 22q11 deletion syndrome and identified 43 distinct features present in more than 5% of patients. Common characteristic features included intellectual disabilities (92.3%), hypocalcemia (64%), palatal anomalies (42%), and cardiovascular anomalies (25.8%). Other less commonly appreciated features included obesity (35%), hypothyroidism (20.5%), hearing deficits (28%), cholelithiasis (19%), scoliosis (47%), and dermatologic abnormalities (severe acne, 23%; seborrhea, 35%). Significantly, schizophrenia was present in 22.6% of patients.

Neuropsychologic Features

Golding-Kushner et al. (1985) observed that children with VCFS had 'characteristic personality features,' which were described as blunt or inappropriate affect, and that a greater than expected number of these children developed severe psychiatric illnesses as they approached adolescence.

Shprintzen et al. (1992) pointed out that psychotic illness is a feature of VCFS in adolescents or adults. In a pilot study of patients diagnosed with VCFS and their relatives, Pulver et al. (1994) found a high rate of psychosis among the patients and their relatives, suggesting that there may be a gene associated with schizophrenia (see 181500) on chromosome 22q or that a DNA rearrangement in this region may be important to the etiology of some forms of schizophrenia.

Kok and Solman (1995) emphasized the usefulness of interactive computer-based instruction for the development of reading, language, spelling, and numeracy skills in VCFS individuals.

Woodin et al. (2001) reported updated findings of neuropsychologic data from 80 children with the 22q11 deletion. The subjects showed higher verbal than nonverbal IQ scores, assets in verbal memory, and deficits in the areas of attention, story memory, visuospatial memory, arithmetic performance relative to other areas of achievement, and psychosocial functioning.

Gothelf et al. (2004) studied 43 patients with VCFS for obsessive-compulsive symptoms, using the Yale-Brown obsessive compulsive scale and a semistructured psychiatric interview. Fourteen of the subjects (32.6%) met DSM-IV criteria for obsessive-compulsive disorder (OCD; see 164230); in these patients, the symptoms began at an early age and generally responded to fluoxetine treatment. Additionally, 16 of the patients (37.2%) had attention-deficit hyperactivity disorder (ADHD; see 143465) and 7 (16.2%) had a psychotic disorder.

Gothelf et al. (2004) investigated the association of familial, developmental, and physical factors with the occurrence of ADHD in 51 patients with nonfamilial VCFS. Twenty-one patients (41.2%) were diagnosed with ADHD. There was a significantly greater prevalence of ADHD in the first-degree relatives of patients with ADHD than in those without (odds ratio, 5.9, 95% CI, 1.6-22.1; p = 0.006). ADHD and non-ADHD groups had similar IQ scores (total, verbal, and performance) and had a similar average degree of severity of facial dysmorphism and cardiac and cleft anomalies. Gothelf et al. (2004) suggested that there is a genetic contribution to ADHD in VCFS.

Evers et al. (2006) reported a 52-year-old man with 22q11.2 deletion. As a child he showed learning disabilities and behavioral problems. As a young adult, he exhibited aggressive outbursts, apathy, echolalia, perseverations, and psychotic features, including delusional thoughts and hallucinations, necessitating long-term care in a psychiatric facility. Since then, he has demonstrated aggressive behavior, periods of withdrawal, and progressive cognitive decline consistent with dementia, particularly since the age of 36 years. An affected autistic sister also had the deletion.

Evers et al. (2009) reported 7 unrelated adult patients with the 22q11.2 deletion and low cognitive function. Most had psychotic episodes in their young adult lives followed by intellectual decline. Other variable features included paranoia, aggression, mood swings, destructive behavior, autistic disorder, and dementia. At the time of the report, all were living in long-term residential care. All presented with intellectual disability, which later developed into more severe psychiatric illnesses, leading to the correct molecular diagnosis later in life.

Butcher et al. (2012) used the Vineland Adaptive Behavior Scales to assess functioning in 100 adults with 22q11.2 deletion syndrome (46 males; mean age = 28.8 (SD = 9.7) years) where intellect ranged from average to borderline (57 individuals) to mild intellectual disability (43 individuals). More than 75% of the subjects scored in the functional deficit range. Although personal, vocational, and financial demographics confirmed widespread functional impairment, daily living skills and employment were relative strengths. Intelligence quotient was a significant predictor (p less than 0.001) of overall and domain-specific adaptive functioning skills. A diagnosis of schizophrenia was a significant predictor (p less than 0.05) of overall adaptive functioning, daily living skills, and socialization scores. Notably, congenital heart disease, history of mood/anxiety disorders, sex, and age were not significant predictors of functioning. Butcher et al. (2012) concluded that, despite functional impairment in adulthood that is primarily mediated by cognitive and psychiatric phenotypes, relative strengths in activities of daily living and employment have important implications for services and long-term planning in patients with 22q11.2 deletion syndrome.

Van et al. (2016) investigated the relationship of small for gestational age (SGA) birth weight (less than 3rd percentile for sex and gestational age) and prematurity (less than 37 weeks' gestation) to expression of schizophrenia in a well-characterized cohort of 123 adults with 22q11 deletion syndrome. SGA birth weight (OR = 3.52, 95% CI 1.34-9.22) and prematurity (OR = 5.38, 95% CI = 1.63-17.75), but not maternal factors, were significant risk factors for schizophrenia in 22q11.2 deletion syndrome. Being born SGA or premature resulted in a positive predictive value of 46% for schizophrenia; negative predictive value in the absence of both features was 83%. Post hoc analyses suggested that these perinatal complications were also associated with factors indicative of increased severity of schizophrenia. Van et al. (2016) concluded that in 22q11.2 deletion syndrome, fetal growth and gestation may have a clinically significant impact on future risk of schizophrenia.

Biochemical Features

Goodman et al. (2000) reported that 8 of 15 patients with deletions in the VCF critical region 22q11.2 had elevated proline levels ranging from 278 to 849 micromol/l while 7 were in the normal range of 51 to 271 micromol/l. Goodman et al. (2000) suggested that the hyperprolinemia (239500) is caused by the hemizygous deletion of the proline oxidase gene (606810) that maps to this region. Goodman et al. (2000) concluded that elevations in plasma proline levels should be considered a biochemical feature of the chromosome 22q11.2 deletion syndromes and suggested that patients with isolated hyperprolinemia should be studied for the microdeletion at 22q11.2.

Diagnosis

VCFS is the most common syndrome that has palatal anomalies as a major feature. A possible strategy for early detection of VCFS is the routine screening for 22q11 deletions in all infants with cleft palate (CP). Ruiter et al. (2003) evaluated this strategy as opposed to testing on clinical suspicion alone. At the Nijmegen Cleft Palate Craniofacial Center in the Netherlands, they routinely tested 58 new patients with overt CP, using FISH, for the 22q11 deletion. One deletion was identified in a newborn girl with an overt CP who was clinically not suspected of having VCFS. Based on this study and the literature, they estimated the prevalence of 22q11 deletions among children with CP, but without any other symptoms of VCFS, to be 1 in 99. They concluded that routine FISH testing for 22q11 deletions in infants with overt CP is not indicated, provided clinical follow-up is guaranteed.

Cytogenetics

The large clinical overlap between DiGeorge syndrome and velocardiofacial syndrome suggested an etiologic connection. DiGeorge syndrome is associated with microdeletions of chromosome 22q11 and is thought to be caused by reduced dosage of genes within this region, i.e., monosomy. Scambler et al. (1992) presented preliminary evidence of similar microdeletions in 22q11 in patients with VCF syndrome. Kelly et al. (1993) found monosomy for a region of 22q11 in all 12 patients with VCFS who were examined by use of DNA probes. By high-resolution banding techniques, Driscoll et al. (1992) detected an interstitial deletion of 22q11.21-q11.23 in 3 of 15 patients with VCFS. The remaining 12 patients had apparently normal chromosomes. Molecular analysis with probes from the DiGeorge chromosome region (DGCR) within 22q11 detected DNA deletions in 14 of the 15 patients. In 2 families, deletions were detected in the affected parent as well as the proband, suggesting autosomal dominant transmission of VCFS due to segregation of a deletion. Thus, further support is provided that VCFS and DGS may be the result of mutation in the same gene.

Karayiorgou et al. (1995) reported the results of 2 studies examining the genetic overlap between schizophrenia and VCFS. In the first study, they characterized 2 interstitial deletions identified on 22q11 in a sample of schizophrenic patients. The size of the deletions were estimated to be between 1.5 and 2 Mb. In the second study, they investigated whether variations in deletion size are associated with the schizophrenic phenotype in VCFS patients. The results suggested that a region of the genome that had previously been implicated by genetic linkage analysis may harbor genetic lesions that increase the susceptibility to schizophrenia. See 600850.

To ascertain the relationship between psychiatric illness, VCFS, and chromosome 22 deletions, Carlson et al. (1997) evaluated 26 VCFS patients by clinical and molecular biologic methods. The VCFS children and adolescents were found to share psychiatric disorders, including bipolar spectrum disorders and attention-deficit disorder with hyperactivity. The adult patients (more than 18 years of age) were affected with bipolar spectrum disorders. Four of 6 adult patients had psychotic symptoms manifested by paranoid and grandiose delusions. Loss of heterozygosity (LOH) analysis of all 26 patients revealed that all but 3 had a large 3-Mb common deletion. One patient had a nested distal deletion and 2 did not have a detectable deletion, even when analyzed with a large number of sequence tagged sites (STSs) at a resolution of 21 kb. There was no correlation between the phenotype and the presence of the deletion within 22q11. The remarkably high prevalence of bipolar spectrum disorders, in association with the congenital anomalies of VCFS and its occurrence among nondeleted VCFS patients, suggested a common genetic etiology.

Morrow et al. (1995) used 11 short tandem-repeat polymorphic (STRP) markers to study 15 VCFS individuals and their unaffected parents. Haplotypes generated by these markers revealed that 82% of the patients had deletions. All patients who had a deletion shared a common proximal breakpoint, while there were 2 distinct distal breakpoints. Markers D22S941 and D22S944 appeared to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. Parental origin of the deleted chromosome had no effect on the phenotypic manifestations.

By genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11, Carlson et al. (1997) found that 83% had a deletion and more than 90% of these had a similar deletion of approximately 3 Mb, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. They found no correlation between the presence or size of the deletion and the phenotype. To define further the chromosomal breakpoints among the VCFS patients, they developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that included deletion breakpoints was constructed, incorporating genes and ESTs isolated by the hybridization selection method. The ordered markers were used to examine the 2 separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, they could map the chromosome breakpoints within a single cosmid.

Edelmann et al. (1999) developed hamster-human somatic hybrid cell lines from VCFS/DGS patients and showed by use of haplotype analysis with a set of 16 ordered genetic markers on 22q11 that the breakpoints occurred within similar low copy repeats, designated LCR22s. Models were presented to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders.

Shaikh et al. (2000) completed sequencing of the 3-Mb typically deleted region (TDR) and identified 4 LCRs within it. Although the LCRs differed in content and organization of shared modules, those modules that were common between them shared 97 to 98% sequence identity with one another. Sequence analysis of rearranged junction fragments from variant deletions in 3 DGS/VCFS patients implicated the LCRs directly in the formation of 22q11.2 deletions. FISH analysis of nonhuman primates suggested that the duplication events which generated the nest of LCRs may have occurred at least 20 to 25 million years ago.

Saitta et al. (2004) traced the grandparental origin of regions flanking de novo 3-Mb deletions in 20 informative 3-generation families with DiGeorge or velocardiofacial syndromes. Haplotype reconstruction of the flanking regions showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19 of 20 families, whereas the normal chromosome 22 in these probands showed interchromosomal exchanges in 2 of 15 informative meioses, a rate consistent with the genetic distance. Immunostaining with MLH1 (120436) antibody localized meiotic exchanges to the distal region of chromosome 22q in 75% of human spermatocytes tested, also reflecting the genetic map. There was no effect of proband gender or parental age on crossover frequency, and parental origin studies in 65 de novo 3-Mb deletions demonstrated no bias. Unlike Williams syndrome (194050), FISH analysis showed no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11-deleted patients or in 8 nondeleted patients with a DGS/VCFS phenotype. Saitta et al. (2004) concluded that significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 are the likely etiology for these deletions. Since this type of exchange occurs more often for 22q11 deletions than for deletions of 7q11, 15q11, 17p11, and 17q11, they suggested that there is a difference in the meiotic behavior of chromosome 22.

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (see also 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) identified the 22q11.2 microdeletion in 186 individuals; 38 were de novo, 4 maternally inherited, 4 paternally inherited, and 140 of unknown inheritance. The average age at diagnosis was 7.1 years with an age range of 0.2 to 50.1 years, and the indications for study included development delay, behavioral abnormalities, dysmorphic features, multiple congenital anomalies, congenital heart defect, failure to thrive, autism, hypocalcemia, seizure disorder, postaxial polydactyly, and clubfeet. This deletion was seen in 115 of 23,250 cases referred to their laboratory for a frequency of 0.49%, and not at all in 5,674 controls for a p value of less than 0.0001 (see Itsara et al., 2009). The incidence in a schizophrenia population reported by Kirov et al. (2009) was 0.2% compared to 0.0% in their controls. Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions.

Heterogeneity

Tsai et al. (1999) reported a child with congenital heart disease (atrial septal defect, ventricular septal defect, pulmonic stenosis), submucosal cleft palate, hypernasal speech, learning difficulties, and right fifth finger anomaly, features consistent with velocardiofacial syndrome. The child did not have a 22q deletion based on FISH analysis using the probe D22S75; however, cytogenetic analysis demonstrated a terminal deletion of 4q34.2-qter. The authors suggested that a distal 4q deletion may lead to a syndrome similar to velocardiofacial syndrome and emphasized the importance of searching for other chromosome abnormalities when a phenotype of velocardiofacial syndrome is present and a 22q deletion is not detected.

Van Esch et al. (1999) reviewed 35 cases of del10p13-p14 plus one of their own (see 601362) and compared the phenotypic spectrum with that of classic DGS/VCFS associated with del22q11 as defined by Ryan et al. (1997). Both groups of patients may have facial dysmorphism, renal anomalies, hypoparathyroidism, and immune defect. However, severe growth and mental retardation were noted in almost all patients with del10p but not in those with del22q11. Heart defects were less frequent in del10p. A distinct feature in del10p was the presence of progressive sensorineural deafness, whereas in del22q11 the hearing loss was mostly conductive due to palate deformities and velopharyngeal insufficiency. In both groups, the full clinical picture was rarely seen.

Inheritance

Carelle-Calmels et al. (2009) noted that deletion of 22q11.2, resulting in DGS or VCFS, is usually sporadic but has been reported to be inherited in 6 to 28% of patients with these syndromes. They performed cytogenetic studies of the parents of a girl with DGS (or VCFS) who had a deletion of 22q11.2 and found an unexpected rearrangement of both 22q11.2 regions in the unaffected father. He carried a 22q11.2 deletion on one copy of chromosome 22 and a reciprocal 22q11.2 duplication (see 608363) on the other copy of chromosome 22. Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the 22q11 deletion syndrome. Carelle-Calmels et al. (2009) noted that this finding has implications for genetic counseling.

Delio et al. (2013) genotyped a total of 389 DNA samples from 22q11 deletion syndrome-affected families. A total of 219 (56%) individuals with 22q11 deletion had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, similar to data for the general population in 11 countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6 to 1.7 times greater than that for males, suggesting that for this region in the genome enhanced meiotic recombination rates, as well as other 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

Molecular Genetics

Using a YAC clone containing the VCFS critical region on chromosome 22q11 as a substrate for cDNA selection, Sirotkin et al. (1996) derived a cDNA that encodes a clathrin heavy chain gene (CLTD; 601273). FISH studies revealed that a cosmid containing the CLTD gene mapped to chromosome 22q11 and was deleted from 2 patients with VCFS who had previously been shown to have deletions of chromosome 22q11. Sirotkin et al. (1996) noted that because VCFS is a complex disorder with significant variability in phenotype and penetrance, it is likely that a number of genes in the commonly deleted region contribute to the phenotype.

Sirotkin et al. (1997) identified a novel gene, termed transmembrane protein deleted in VCFS (TMVCF; 602101), in the VCFS critical region. They localized the TMVCF gene between polymorphic markers D22S944 and D22S941, both of which are deleted in more than 80% of VCFS patients.

Carlson et al. (1997) delineated a 480-kb critical region for VCFS, including the genes for GSCL (601845), SLC25A1 (190315), CLTD, HIRA (600237), and TMVCF, as well as a number of novel ordered ESTs.

Dunham et al. (1992) pointed out that the HP500 sequence often deleted in VCFS is located within the same 450-kb yeast artificial chromosome (YAC) as the catechol-O-methyltransferase (COMT; 116790) gene, which might, therefore, be deleted also in this disorder.

Murphy et al. (1999) examined 50 adults with VCFS using a structured clinical interview to establish a DSM-IV diagnosis. Twelve percent of this sample of 50 patients were referred from a psychiatry clinic; the remainder came from genetics or cardiology. Fifteen individuals with VCFS (30%) had a psychotic disorder, with 12 (24%) fulfilling DSM-IV criteria for schizophrenia. In addition, 6 (12%) had major depression without psychotic features. The individuals with schizophrenia had fewer negative symptoms and a relatively later age of onset compared with those with schizophrenia without VCFS. Murphy et al. (1999) found no evidence that possession of the low-activity COMT allele (val158-to-met; 116790.0001) was associated with schizophrenia in their sample.

Baker et al. (2005) studied 2 hypotheses: first, that individuals with 22q11 deletion syndrome would manifest specific cognitive and neurophysiologic abnormalities in common with individuals at high risk for schizophrenia in the general population; and second, that the COMT val108/158met polymorphism would modify the severity of endophenotypic features. Adolescents and young adults with 22q11 deletion syndrome, aged 13-21, were compared with age- and IQ-matched control subjects on measures that were associated with risk for idiopathic schizophrenia. These individuals displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity event-related potentials were reduced at frontal electrodes but intact at temporal sites. The presence of the COMT val108/158met allele on the single intact chromosome 22 was associated with more marked auditory mismatch negativity amplitude reduction and poorer neuropsychologic performance. Neither allele influenced psychiatric symptoms.

Glaser et al. (2006) tested measures of executive function, IQ, and memory in 34 children and young adults with the 22q11.2 deletion syndrome (14 hemizygous for COMT val158 and 30 for met158). No significant differences were detected between met- and val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. Glaser et al. (2006) suggested that either the COMT polymorphism has a small effect on executive function in 22q11.2 deletion syndrome or no effect exists at all.

Yagi et al. (2003) demonstrated mutations in the TBX1 gene in patients with the conotruncal anomaly face syndrome (217095)/velocardiofacial syndrome (602054.0001 and 602054.0003).

Paylor et al. (2006) identified a heterozygous 23-bp deletion in the TBX1 gene (602054.0004) in a mother and 2 sons with velocardiofacial syndrome. The mother had major depression (608516) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., 608638 and 209850). Paylor et al. (2006) suggested that the Tbx1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 22q11.2 deletion was identified in 93 cases and no controls for a p value of 9.15 x 10(-21) and a frequency in cases of 1 of 169.

Genotype/Phenotype Correlations

McDonald-McGinn et al. (2001) reported on 30 individuals with the 22q11 deletion that were identified following the diagnosis in a relative. Sixty percent of patients had no visceral anomalies. In fact, only 6 of the 19 adults (32%) and 6 of the 11 children (55%) had major findings which would have brought them to medical attention. Deletion sizing demonstrated the same large 3- to 4-Mb deletion in most families despite wide inter- and intrafamilial variability