Alternative titles; symbols
SNOMEDCT: 56604005; ORPHA: 193, 217315; DO: 0111590;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q22.2 | Cohen syndrome | 216550 | Autosomal recessive | 3 | VPS13B | 607817 |
A number sign (#) is used with this entry because of evidence that some patients with Cohen syndrome have homozygous or compound heterozygous mutations in the COH1 gene (VPS13B; 607817) on chromosome 8q22.
Cohen syndrome is an autosomal recessive multisystem disorder characterized by many clinical features, including facial dysmorphism, microcephaly, truncal obesity, impaired intellectual development, progressive retinopathy, and intermittent congenital neutropenia (summary by Duplomb et al., 2014).
Cohen syndrome is one of the rare autosomal recessive disorders that are overrepresented in the Finnish population (Norio, 2003). The phenotype in Finnish patients is highly homogeneous, consisting of nonprogressive mild to severe psychomotor retardation, motor clumsiness, microcephaly, characteristic facial features, childhood hypotonia and joint laxity, progressive retinochoroidal dystrophy, myopia, intermittent isolated neutropenia, and a cheerful disposition. Characteristic facial features include high-arched or wave-shaped eyelids, a short philtrum, thick hair, and low hairline. Kolehmainen et al. (2003) stated that in non-Finnish patients thought to have Cohen syndrome, a confusing phenotypic variability prevails. Obesity, although frequently mentioned as a characteristic finding, is insignificant. On the other hand, there is no proof of retinochoroidal dystrophy or intermittent neutropenia in reports of some patients. Chandler et al. (2003) studied 33 non-Finnish patients with Cohen syndrome and concluded that Cohen syndrome has a distinctive clinical phenotype identifiable not only in Finnish patients but also in other genetically diverse patient groups.
Cohen et al. (1973) described a brother and sister and an unrelated patient with hypotonia, obesity, high nasal bridge, and prominent incisors as well as mental deficiency. Carey and Hall (1978) reported 4 additional patients. Sack and Friedman (1980) observed the syndrome in a 10-year-old girl with excessive height and floppy mitral valve. Intrafamilial variability suggested that the diagnosis may often be difficult. Kousseff (1981) described 4 affected sibs (2 of each sex) with moderate mental retardation, microcephaly, hypotonia, high nasal bridge, and narrow hands and feet with elongated fingers and toes. Three sibs were short of stature. Friedman and Sack (1982) reported 5 additional cases in 4 families, strengthening the conclusion of autosomal recessive inheritance. Mental retardation, high nasal bridge, prominent central incisors with open mouth, maxillary malar hypoplasia, and downslanting palpebral fissures were features. They suggested that the disorder may have a relatively high frequency in Ashkenazi Jews.
Since 1968, Norio et al. (1984) had observed patients with the same disorder, known by them as the 'Pepper syndrome,' from the family name. By 1984, they found reports of 25 cases (Balestrazzi et al., 1980; Goecke et al., 1982) and added 6 Finnish patients. Norio et al. (1984) added chorioretinal dystrophy and granulocytopenia to the clinical features and observed parental consanguinity in 2 instances. Ophthalmologic findings included decreased visual acuity, hemeralopia (see 310500 for a discussion of the use of the terms hemeralopia and nyctalopia), constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram.
Fuhrmann-Rieger et al. (1984) pointed out the similarities of the Prader-Willi syndrome (176270) and Cohen syndrome. (See also Fraccaro et al., 1983).
North et al. (1985) reported 6 cases in 4 sibships. Periureteric obstruction and epilepsy were reported as possible new features. In Israel, where the Cohen syndrome seems to be unusually frequent, Sack and Friedman (1986) studied 39 patients in 32 families. Neutropenia and chorioretinal dysplasia, 2 manifestations found in all Finnish patients by Norio et al. (1984), were not found in any of these patients. Incorrect diagnoses included Marfan syndrome, Sotos syndrome, hypothyroidism, minimal brain dysfunction, and, most frequently, 'mental retardation of an unknown cause,' illustrating the difficulty of being certain of the diagnosis.
Young and Moore (1987) described 3 affected sibs. Abnormalities present in all 3 children included mental retardation, hypotonia, and short philtrum with open mouth and prominent lips. Whereas the 2 older sibs had similar facies and an engaging personality, the youngest had a different facial appearance and marked behavioral problems. Mehes et al. (1988) found mitral valve prolapse and severe gastroesophageal reflux with hiatal hernia in an affected girl aged 2 years and 4 months. These observations, along with others previously reported, suggested that Cohen syndrome may be a connective tissue disorder.
Kondo et al. (1990) described 2 affected brothers from a consanguineous marriage who also had leukopenia and mottled retina. Kondo et al. (1990) pointed out that mottled retina had been observed in 22 of 87 patients and that it appears to be family- and ethnic-specific. Among 19 familial cases, mottled retina was observed in all affected sibs from 5 families, but in 13 families none of the affected sibs had mottled retinas. All Finnish patients had the mottled retina, but this was noted in only 1 of 39 Jewish patients. Based on these observations, Kondo et al. (1990) suggested that there are 2 alleles at the gene locus for the Cohen syndrome: one for a Finnish type with mottled retina and the other for a Jewish type without retinal anomalies. They concurred with Norio and Raitta (1986) that the Mirhosseini-Holmes-Walton syndrome (268050) is the same as Cohen syndrome, or at least an allelic disorder.
Steinlein et al. (1991) described 2 brothers with findings fitting the diagnosis of both the Cohen and the Mirhosseini-Holmes-Walton syndromes but also showing severe ocular manifestations. Tapetoretinal degeneration was documented by histopathologic studies. The younger brother suffered total retinal detachment bilaterally, requiring enucleation.
Warburg et al. (1990) were of the opinion that a retinitis pigmentosa-like tapetoretinal degeneration is an 'obligatory sign' in patients with Cohen syndrome. Their patient also had granulocytopenia.
Massa et al. (1991) described isolated growth hormone deficiency in a girl with Cohen syndrome. Satisfactory catch-up growth occurred after treatment with biosynthetic human growth hormone. Fryns et al. (1991) reported a successful pregnancy in a 26-year-old woman with presumed Cohen syndrome. Her offspring had slight psychomotor retardation but was not thought to have the Cohen syndrome.
Norio (1993) indicated that the diagnosis of Cohen syndrome is suggested by the short philtrum (which is unable to cover the upper incisors), prominent root of the nose, and prominent upper central incisors. The feet are often small, and there is usually an increased space between toes 1 and 2 ('sandal groove'). The neutropenia is intermittent and harmless.
Higgins et al. (1994) demonstrated pyridoxine-responsive hyper-beta-alaninemia in a 4-year-old girl with some features of Cohen syndrome. She had crooked teeth, a small philtrum, narrow hands, and global developmental delay. Ophthalmic examination was not reported and there was no mention of obesity.
Schlichtemeier et al. (1994) described probable Cohen syndrome in African American brother and sister. The brother, who presented at age 13 years with new-onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs, showed combined deficiency of protein C, protein S, and antithrombin III. Carotid aneurysm and tortuous descending aorta were also present. Schlichtemeier et al. (1994) suggested that vasculopathy may be an integral part of the Cohen syndrome.
North et al. (1995) reported the cases of identical female twins with Cohen syndrome. They presented with retinal degeneration, obesity, and mental retardation, and had the characteristic facial appearance. Unusual features of the twins included tall stature, macrocephaly, and transient cardiomyopathy during the first year of life. Precocious puberty was present in both girls; the development of breast buds and axillary hair was noted at the age 7.5 years.
Kivitie-Kallio et al. (1997) reported hematologic data on 26 Finnish patients with Cohen syndrome. All had experienced periods of isolated granulocytopenia from an early age. Granulocytopenia was mild to moderate, noncyclic, and never fatal. Most patients suffered from prolonged or repeated gingival or skin infections. In 16 patients studied in detail, bone marrow examination showed a normo- or hypercellular marrow, with a left-shifted granulopoiesis in 8 of the 16 patients. The response to adrenaline stimulation was subnormal in 12 of 14 and to hydrocortisone in 8 of 16 patients, but administration of recombinant GCSF (138970) caused granulocytosis in the 3 patients studied. No bone marrow malignancies were seen.
Olivieri et al. (1998) studied the bone marrow and the functional properties of neutrophils obtained from peripheral blood or skin window exudates from a patient with Cohen syndrome. Neutrophil adhesive capability was greatly increased in this patient. Cytofluorometric expression of CD11B (120980) and CD62L molecules were consistent with a generalized neutrophil activation in vivo. The patient was a 22-year-old girl with neutropenia and recurrent gingivitis. A tentative diagnosis of Prader-Willi syndrome had been made in childhood. However, her features, including obesity, hypotonia, microcephaly, chorioretinal dystrophy, high nasal bridge, narrow hands and feet, narrow and high-arched palate, and prominent central incisors, were more consistent with Cohen syndrome.
In 3 patients with Cohen syndrome, Okamoto et al. (1998) found a remarkably high level of urinary hyaluronic acid. They pointed out that hyperhyaluronic aciduria is a characteristic finding in Werner syndrome (277700) and some other conditions. Okamoto et al. (1998) suggested that the basic defect in Cohen syndrome involves a metabolic abnormality in the extracellular matrix.
Kivitie-Kallio et al. (1998) performed MRI on 18 patients with Cohen syndrome and 26 healthy volunteers. The main finding was a relatively enlarged corpus callosum. A relatively enlarged corpus callosum in a microcephalic head and normal signal intensities of the gray and white matters supports a clinical suspicion of Cohen syndrome.
Kivitie-Kallio et al. (1999) evaluated cardiac, endocrine, and radiologic abnormalities in 22 patients of Finnish descent with Cohen syndrome. No evidence for clinically significant mitral prolapse was found; however, a decreased left ventricular function with advancing age was identified. No significant endocrine abnormalities were found in examination of pituitary, adrenal, and thyroid function. The patients were either of normal height or were moderately short at all ages, often associated with marked kyphosis. Truncal obesity was seen in 4 of the 22 patients. X-rays of the chest, lumbar and thoracic spine, long bones, ankles, and metacarpophalangeal pattern profiles revealed kyphosis, scoliosis, and calcaneo planovalgus as common features. Fingers of these patients were slender but short with a characteristic metacarpophalangeal pattern profile.
Horn et al. (2000) reported 2 brothers and a cousin from a multiply consanguineous kindred of Lebanese descent with a syndrome of microcephaly, progressive postnatal growth deficiency, mental retardation, hypotonia, chorioretinal dystrophy, and myopia. The severity of the condition varied among the affected family members. Horn et al. (2000) suggested that the syndrome they reported, the Cohen syndrome, and the Mirhosseini-Holmes-Walton syndrome may be the same or allelic disorders.
Kivitie-Kallio et al. (2000) reported ophthalmologic findings from 22 Finnish patients with Cohen syndrome.
Hurmerinta et al. (2002) pointed to the fact that Cohen syndrome is relatively common in Finland, where 35 patients had been diagnosed. They obtained anthropometric measurements of the head and face of 22 patients, and cephalometric radiographs of 14 patients. Anthropometric analysis confirmed and quantified the small head size. Width of the upper face was close to normal but width of the lower face was small. The philtrum was shorter than in healthy controls. Measurements from standardized radiographs showed short cranial base dimensions but normal cranial base angles. Most patients had forward-inclined upper incisors and maxillary prognathia.
De Ravel et al. (2002) reevaluated a brother and sister, the offspring of first cousins, who were originally reported by Buntinx et al. (1991) as representing an apparently new syndrome of mental retardation, short stature, unusual face, radioulnar synostosis, and retinal pigment abnormalities. De Ravel et al. (2002) concluded that the 55-year-old brother and 52-year-old sister had Cohen syndrome. Both had neutropenia and the male had persistent fluctuating thrombocytopenia. De Ravel et al. (2002) stated that asymptomatic thrombocytopenia had not previously been reported in Cohen syndrome.
In their series of 33 non-Finnish patients with Cohen syndrome, Chandler et al. (2003) identified laryngeal abnormalities, including laryngomalacia, laryngeal stenosis, and vocal cord paralysis, as an associated feature.
Karpf et al. (2004) reported findings on cognitive, linguistic, and adaptive profiles in a group of 45 individuals clinically diagnosed with Cohen syndrome at ages varying from 4 to 49 years. Independence levels were generally poor, but socialization skills were relatively less impaired. This particular area of strength was thought to underlie the 'sociable' temperament typically associated with Cohen syndrome. The range of cognitive ability was wider in this study than reported in most previous studies, raising the issue of whether mental retardation should be considered a necessary component of the phenotype.
Kolehmainen et al. (2004) undertook an extensive molecular assessment of 76 patients from 59 families with a provisional diagnosis of Cohen syndrome and correlated molecular and clinical findings. The patients were assessed for the following 8 clinical criteria: developmental delay, microcephaly, typical Cohen syndrome facial gestalt, truncal obesity with slender extremities, overly sociable behavior, joint hypermobility, high myopia and/or retinal dystrophy, and neutropenia. Patients fulfilling 6 or more criteria were considered likely to have true Cohen syndrome. Those with lower scores (5 of 8 or fewer) were considered provisionally to have a Cohen-like syndrome. Kolehmainen et al. (2004) found 22 different COH1 mutations, of which 19 were novel, in probands identified by these diagnostic criteria. In addition, they identified another 3 novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who were labeled 'Cohen-like.'
Falk et al. (2004) described 8 members of 2 large Amish kindreds who had early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, and a friendly disposition. Several of the children had intermittent granulocytopenia. Affected individuals shared a common facial appearance involving mild synophrys, hypertelorism, wide and wave-shaped palpebral fissures, low nasal bridge with a pinched root and bulbous tip, smooth philtrum, thin upper lip, and hypotonic facies. They appeared to grimace when smiling. Although the facial gestalt was considered inconsistent with the diagnosis of Cohen syndrome, sequencing of the COH1 gene revealed compound homozygosity in all affected individuals for both a frameshift (607817.0009) and a missense (607817.0010) mutation in the COH1 gene. Falk et al. (2004) concluded that facial gestalt is an unreliable indicator of Cohen syndrome between ethnic populations, although it is consistent among affected individuals within a particular ethnic group.
Waite et al. (2010) reported 3 patients, including 2 patients of Pakistani descent from a consanguineous kindred who were distally related, with genetically confirmed Cohen syndrome. All had the typical facial appearance, developmental delay, and ocular anomalies, and all also had cerebellar hypoplasia on brain imaging, which Waite et al. (2010) concluded may be a feature of this disorder.
Rivera-Brugues et al. (2011) reported 3 patients with genetically confirmed Cohen syndrome who were younger than 3 years of age. None had neutropenia, and only 1 had mildly increased pigmentation of the retina. Common features included hypotonic facial expression, almond-shaped eyes, prominent nose, short philtrum, delayed psychomotor development, and mental retardation. The authors noted that the facial phenotype and some additional features of the disorder change with time.
Clinical Variability
Gueneau et al. (2014) described a 33-year-old woman who had recurrent infections in infancy and childhood and was diagnosed with chronic and intermittent neutropenia. Speech and motor development was normal. At 25 years of age, she had reduced visual fields and retinal abnormalities, and was diagnosed with retinal dystrophy. Upon examination at 33 years of age, she had short stature, borderline microcephaly, and the typical facial gestalt for Cohen syndrome: facial dysmorphism included moderately downslanting palpebral fissures, convex and high nasal bridge, malar hypoplasia, short philtrum, and mild ptosis. She had slender extremities but no joint hypermobility or truncal obesity. In addition, her intellectual development was normal; she had attended high school and had a reported IQ of 100. Funduscopy revealed moderate pigmentary retinopathy with rare bone spicule-shaped pigment deposits in the periphery and macular edema. Electroretinography revealed severely decreased responses in both scotopic and photopic conditions, indicating that both rod and cone photoreceptor responses were impaired.
Megarbane et al. (2001) described a nonconsanguineous Lebanese family in which 2 brothers had a seemingly distinct syndrome comprising microcephaly, primary cutis verticis gyrata, progressive retinitis pigmentosa, cataracts, sensorineural hearing loss, and mental retardation. The brothers were 41 and 53 years of age. In the older brother the scalp features had appeared 10 years earlier. In the younger brother visual problems became obvious at age 12 and the auditory problem at age 30. Night blindness had been noted from age 20. By a genomewide scan in this family, Megarbane et al. (2009) found a region of homozygosity by descent in the region of chromosome 8 containing the VPS13B gene. Sequencing of this gene identified a homozygous mutation (607817.0016) in the affected brothers that segregated with the disorder in the family. Megarbane et al. (2009) noted that the features in the brothers were compatible with Cohen syndrome with the additional features of cutis verticis gyrata and sensorineural deafness. They also noted that the hearing loss and cutis verticis gyrata could be caused by mutations in a different gene and locus, but that their linkage data did not support the presence of another causative homozygous locus and no deafness gene or locus had been identified on chromosome 8q. Because cutis verticis gyrata is frequently associated with mental retardation, they suggested that it may be a rare manifestation of Cohen syndrome.
Duplomb et al. (2014) found that the serum proteins of 11 patients with genetically confirmed Cohen syndrome showed an unusual pattern of glycosylation characterized by a significant accumulation of agalactosylated fucosylated structures, as well as asialylated fucosylated structures, suggesting a defect of N-glycosylation in the Golgi. Glycosylation of the intracellular proteins ICAM1 (147840) and LAMP2 (309060) also showed an abnormal profile pattern. However, serum transferrin and a alpha-1-antitrypsin (SERPINA1; 107400) were normal. In vitro knockdown of VPS13B confirmed these glycosylation defects. Patient fibroblasts showed alterations in Golgi morphology, decreased or absent early endosomes, and abnormally enlarged lysosomes, suggesting a crucial role for VPS13B in endosomal-lysosomal trafficking. The findings indicated that Cohen syndrome is associated with major glycosylation defects, which may contribute to the phenotype.
Kivitie-Kallio and Norio (2001) reported the results of their nationwide study of 29 patients with Cohen syndrome in Finland. They found the following features to be essential for the diagnosis: nonprogressive psychomotor retardation, motor clumsiness, and microcephaly; typical facial features including high-arched eyelids, short philtrum, thick hair, and low hairline; childhood hypotonia and hyperextensibility of the joints; ophthalmologic findings of retinochoroidal dystrophy and myopia in patients over 5 years of age; and periods of isolated granulocytopenia. They noted a changing phenotype with age. In their patients, psychomotor retardation was profound in 22%, severe in 61%, moderate in 6%, and mild in 11%.
On the basis of a study of 33 non-Finnish patients with Cohen syndrome, Chandler et al. (2003) contended that the diagnostic criteria suggested by Kivitie-Kallio and Norio (2001) are important but not obligatory features. As an aid to diagnosis, they proposed the presence of at least 2 of the following major criteria in a child with significant learning difficulties: (1) facial gestalt, characterized by thick hair, eyebrows and eyelashes, wave-shaped, downward-slanting palpebral fissures, prominent, beak-shaped nose, short, upturned philtrum with grimacing expression on smiling; (2) pigmentary retinopathy; and (3) neutropenia. Less specific but supportive criteria included early-onset, progressive myopia; microcephaly; truncal obesity with slender extremities; and joint hyperextensibility.
Limoge et al. (2015) characterized the obesity phenotype in 14 patients with COH1 by examining clinical, glucose, and lipid metabolism features. All patients had truncal obesity, despite a normal BMI in most of them. Although triglyceride, total cholesterol, and LDL values were normal in most patients, HDL was abnormally low in 9 of 13 patients. Leptin was elevated in 8 of 11 patients in whom it was measured, 2 of whom were obese by BMI. Blood pressure was elevated (more than 130/85) in 4 of 8 patients. Fasting blood glucose was normal in 12 of 13 patients, but oral glucose tolerance test showed impaired glucose tolerance after 2 hours in 4 of 9 patients tested. Limoge et al. (2015) also studied primary fibroblasts from COH1 patients as well as SGBS (see 312870) preadipocytes in which expression of VPS13B was knocked down by RNAi, and observed accelerated differentiation into fat cells. This was confirmed by earlier and increased expression of specific adipogenic genes, consequent to the increased response of the cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 (164731) phosphorylation after insulin stimulation, suggestive of insulin resistance. Limoge et al. (2015) concluded that VPS13B is an important regulator of adipogenesis, and that defective VPS13B results in increased fat storage and a risk of type 2 diabetes mellitus in patients with COH1.
In 2 brothers born of consanguineous parents, Kondo et al. (1990) found that Cohen syndrome was not linked to markers in the 15q11-q12 region.
Tahvanainen et al. (1994) mapped the Cohen syndrome locus, symbolized CHS1 by them, to chromosome 8 in an interval of approximately 10 cM between D8S270 and D8S521. Both of these markers had been assigned to 8q22 (Wood et al., 1993). Their studies involved four 2-generation Finnish pedigrees showing uniform clinical features in the affected members. All the remaining 9 patients in Finland were isolated cases in their families. Although not of value for linkage studies, they would be fully informative for the analysis of linkage disequilibrium and haplotype associations. In the Finnish population, one might anticipate a single founding chromosome carrying the disease mutation. Tahvanainen et al. (1994) suggested that the linkage information may help establish or rule out genetic heterogeneity of Cohen syndrome, including answering the question as to whether the ocular findings and leukopenia indicate a separate entity.
By linkage disequilibrium analysis, Kolehmainen et al. (1997) narrowed the COH1 region to the immediate vicinity of D8S1762. Haplotype analysis suggested the occurrence of 1 main COH1 mutation and possibly 1 or 2 rare ones in Finland.
By homozygosity mapping in a consanguineous Lebanese kindred, Horn et al. (2000) localized the gene responsible for this condition to a 26.8-cM region on chromosome 8q21.3-q22.1. This region overlapped the refined gene region for Cohen syndrome (Kolehmainen et al., 1997). Horn et al. (2000) hypothesized that the syndrome in their family, Cohen syndrome, and Mirhosseini-Holmes-Walton syndrome may be allelic.
Segregation analysis in 11 non-Finnish families with Cohen syndrome by Chandler et al. (2003) was consistent with linkage of the disorder to the COH1 critical region on chromosome 8.
Fryns et al. (1990) described a 15-year-old girl with features of Cohen syndrome and a de novo, apparently balanced reciprocal translocation t(5q;7p)(q33.1;p15.1). They suggested that the Cohen syndrome may be due to a mutation in a gene located at either 5q33.1 or 7p15.1.
The transmission pattern of COH1 in the families reported by Kolehmainen et al. (2003) was consistent with autosomal recessive inheritance.
By haplotype analysis, Kolehmainen et al. (2003) refined the critical Cohen syndrome region on 8q22 and characterized a novel gene, COH1, that is mutated in patients with Cohen syndrome (see 607817.0001-607817.0003). In 1 non-Finnish patient with Cohen syndrome studied by Kolehmainen et al. (2003), no mutation was found in the COH1 gene, suggesting genetic heterogeneity.
By segregation analysis in 11 non-Finnish families with Cohen syndrome, Chandler et al. (2003) demonstrated allele sharing in affected but not unaffected sibs within the COH1 critical region. Haplotype analysis suggested the presence of allelic heterogeneity.
Seifert et al. (2006) studied 24 patients with Cohen syndrome from 16 families of varying ethnic backgrounds and identified 25 different mutations in the COH1 gene, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in-frame deletions, and 1 missense mutation. There was marked variability of developmental and growth parameters, although the typical facial gestalt was seen in 23 of 24 patients. Early-onset progressive myopia was present in all the patients older than 5 years, with widespread pigmentary retinopathy seen in 12 of 14 patients assessed who were over 5 years of age.
Katzaki et al. (2007) identified pathogenic mutations in the COH1 gene in 10 Italian patients with Cohen syndrome from 9 families. All patients had characteristic features of the disorder, although with greater variability than reported for Finnish patients. Heterozygous partial COH1 gene deletions were identified in 2 different families.
In 14 individuals with Cohen syndrome from an isolated population on 2 small adjacent islands in the eastern part of the Greek archipelago, Bugiani et al. (2008) identified a large homozygous deletion of exon 6 through 16 in the VPS13B gene (607817.0011). Twelve of the patients belonged to a large consanguineous kindred. The phenotype was relatively homogeneous, with common features including moderate to severe mental retardation, slender extremities with narrow hands and feet, joint hypermobility, and the typical facial gestalt. Microcephaly was not as profound as reported in Finnish patients.
Parri et al. (2010) used multiplex ligation-dependent probe amplification (MLPA) to analyze the VPS13B gene in 14 patients with Cohen syndrome from 11 families, including 4 patients from 3 families previously studied by Katzaki et al. (2007). All 14 patients displayed the typical Cohen facial gestalt, narrow extremities, and truncal adiposity, and microcephaly was present in 9 of the 14 patients. Parri et al. (2010) detected 12 different mutations, including 6 frameshift, 3 splice site, and 2 nonsense mutations, as well as 1 complex rearrangement. Four patients from 3 Italian families carried the same large deletion of exon 6 through 16 previously identified in Greek patients by Bugiani et al. (2008). Haplotype analysis of 1 of the Greek patients as well as the 4 Italian patients suggested that the recurrent deletion is due to an ancestral founder effect in the Mediterranean area.
Using high-density oligonucleotide array data to analyze copy number variation (CNV), Rivera-Brugues et al. (2011) found that 3 of 1,523 patients with unexplained mental retardation had intragenic heterozygous deletions in the COH1 gene. Subsequent sequencing of the COH1 gene revealed point mutations in the second allele in all 3 patients. No CNVs involving the COH1 gene were found in 1,612 controls. The report was an example of how microarrays can be used to identify autosomal recessive syndromes and to extend the phenotypic and mutational spectrum of recessive disorders.
In a 33-year-old woman who exhibited the typical facial gestalt of Cohen syndrome and had neutropenia and retinopathy, but who did not display truncal obesity or mental retardation, Gueneau et al. (2014) identified compound heterozygosity for 2 splice site mutations in the VPS13B gene (607817.0014; 607817.0015). The authors suggested that a dosage effect of residual normal VPS13B protein might explain the incomplete phenotype in this patient.
The preferred symbol for Cohen syndrome is COH1 because the symbol CHS1 had already been established for Chediak-Higashi syndrome (214500).
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