Koolen-De Vries Syndrome

A number sign (#) is used with this entry because Koolen-De Vries syndrome can be caused either by heterozygous mutation in the KANSL1 gene (612452) on chromosome 17q21.31 or by a larger deletion of several genes on chromosome 17q21.31.

See also chromosome 17q21.31 duplication syndrome (613533).

Description

Koolen-De Vries syndrome is characterized by moderate to severe intellectual disability, hypotonia, friendly demeanor, and highly distinctive facial features, including tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. More variable features include cardiac or genitourinary anomalies and seizures (summary by Koolen et al., 2012).

Clinical Features

Using array-based comparative genomic hybridization (array CGH) in a study of 1,200 mentally retarded individuals, Koolen et al. (2006) identified 3 individuals with interstitial, overlapping 17q21.31 microdeletions and a clearly recognizable clinical phenotype of mental retardation, hypotonia, and characteristic face. All 3 individuals showed severe hypotonia from birth onwards, leading to severely delayed motor development. None of the individuals could stand and/or walk before the age of 3 years. Facial features included long hypotonic face with ptosis, blepharophimosis, large and low-set ears, tubular pear-shaped nose with bulbous nasal tip, long columella with hypoplastic alae nasi, and a broad chin. In addition, they all had long fingers, nasal speech, and an amiable and friendly disposition. The deletions encompassed the MAPT (157140) and CRHR1 (122561) genes and were associated with a common inversion polymorphism. All 3 deletions were confirmed by fluorescence in situ hybridization and shown to have arisen de novo.

Koolen et al. (2008) described the clinical and molecular features of 22 patients with 17q21.31 deletion syndrome, including 11 previously reported patients and 11 newly ascertained patients. Common features included developmental delay with mild to moderate mental retardation, characteristic facies with long face, high forehead, large, prominent ears, upward-slanting palpebral fissures, epicanthal folds, bulbous nasal tip, pear-shaped nose, and long, slender features. Other features included cardiac septal defects, seizures, and cryptorchidism. Most patients had a friendly demeanor.

Tan et al. (2009) reported 11 patients with the 17q21.31 deletion syndrome. The facial appearance was characterized by a long face with tall or broad forehead, upslanting palpebral fissures, anteverted ears with thickened or overfolded helices, tubular or pear-shaped nose with bulbous tip, and frequently open mouth. The facial features became more distinctive in early childhood compared to infancy. All patients had hypotonia, global delay, and expressive language delay, and most had a friendly disposition. Congenital cardiac defects included pulmonary stenosis in 3 (27.3%), septal defects in 2 (18.2%), and bicuspid aortic valve in 2 (18.2%), and 1 patient had a dilated aortic root. Other features included urologic anomalies, such as cryptorchidism, hypospadias, vesicoureteric reflux, duplex kidney, renal scarring, and hydronephrosis, and CNS anomalies, such as seizures, corpus callosum defects, and ventriculomegaly. Joint hypermobility and/or hip dislocation/dysplasia were commonly seen, as were ectodermal anomalies of the hair, skin, and teeth. Previously unreported features included persistent fetal fingertip pads, recurrent elbow dislocation, conductive hearing loss, dental abnormalities, and hypertension due to renal scarring.

In a study of copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) compared to CNVs in 8,329 unaffected adult controls, Cooper et al. (2011) identified the 17q21.31 deletion in 23 individuals and atypical deletions in 3 individuals. Detailed clinical information on 2 individuals with the atypical deletion showed typical phenotypic features of the syndrome.

Zollino et al. (2012) reported 2 unrelated girls with Koolen-De Vries syndrome due to de novo heterozygous truncating mutations in the KANSL1 gene (612452.0001 and 612452.0002). Both had failure to thrive in infancy, hypotonia, and delayed psychomotor development. Characteristic facial features included broad forehead, upslanting palpebral fissures, epicanthal folds, 'pear'-shaped nose with bulbous nasal tip, long philtrum, large ears, broad chin, abnormal hair texture, and sparse eyebrows. Both also had joint hyperextensibility. Neither had seizures, heart defects, or urinary anomalies. Both had a happy disposition.

Koolen et al. (2012) reported 2 unrelated patients with Koolen-De Vries syndrome due to de novo heterozygous truncating mutations in the KANSL1 gene (612452.0003 and 612452.0004). Both patients had delayed psychomotor development, intellectual disability, hypotonia, friendly personality, and characteristic facial features, including broad forehead, long face, upslanting palpebral fissures, epicanthal folds, and tubular nose with bulbous nasal tip. Both also had joint laxity, slender lower limbs, pes planus, sacral dimple, and abnormal hair color or texture. One patient had additional features, including cleft lip/palate, ventricular septal defect, cryptorchidism, hypermetropia, strabismus, and scoliosis.

Koolen et al. (2016) compared the clinical features of 45 patients with KDVS, including 33 with a 17q21.31 deletion and 12 with a KANSL1 mutation. Three of the patients had previously been reported. There were no differences of clinical importance between the 2 groups, indicating that haploinsufficiency for KANKL1 is sufficient to cause the core phenotype. However, 44% of those in the deletion group had large ears, compared to none in the mutation group. The patients had strikingly similar dysmorphic features, including long face, upslanting and narrow palpebral fissures, ptosis, epicanthal folds, tubular- or pear-shaped nose with bulbous nasal tip, and everted lower lip. Many had poor overall growth or short stature. Most had hypotonia, particularly in the neonatal period, and all showed delayed development with intellectual disability, ranging from borderline/mild to severe, and speech delay. Expressive language was more severely affected than receptive language, and 4 patients (11%) were nonverbal. About half of patients had seizures that were usually well-controlled, and although the majority (89%) had an amiable affect, about half had neuropsychologic disorders, including hyperactivity, anxiety, autistic features, impulsivity, and depression. Structural brain abnormalities occurred in 53% of patients and mainly consisted of corpus callosum hypoplasia/aplasia, enlarged ventricles, hydrocephalus, and/or heterotopias. Musculoskeletal anomalies were present in 77% of patients, and included tracheo/laryngomalacia, pectus excavatum or carinatum, scoliosis/kyphosis, hip dislocation/dysplasia, joint hypermobility, and positional deformities of the feet. Other common abnormalities included congenital heart defects (39%), urogenital anomalies (45%), and ectodermal abnormalities (67%).

Myers et al. (2017) reviewed the seizure phenotypes of 31 patients with KDVS who had seizures, noting that seizures occur in about 50% of patients with the disorder. The mean age at seizure onset was 3.5 years (range, 4 months to 24 years). Most patients presented with focal impaired awareness and staring spells in infancy, often associated with autonomic signs, such as pallor, vomiting, and oxygen desaturation. Twenty-one patients had prolonged seizures, including status epilepticus. Nine (41%) of 22 patients had refractory seizures, but seizures could be variably controlled in the long term in other patients. EEG studies were available for 26 patients, most of which showed focal or multiform epileptiform discharges; 2 patients had spike-wave discharges with 3-4 Hz frequency. Variable structural brain abnormalities were found in all patients, and mainly included corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles. Less common MRI findings included periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and abnormalities of the brainstem and cerebellum. All individuals had delayed development and intellectual disability, but the degree of cognitive impairment varied, with 6 patients mildly affected, 8 patients moderately affected, and 17 more severely affected.

Mapping

Koolen et al. (2006) found that the deletions in 17q21.31 in 3 mentally retarded individuals were all located within a genomic region that harbors a common 900-kb inversion polymorphism that was previously described by Stefansson et al. (2005) (see 157140). For this region, 2 major and highly divergent haplotypes, designated H1 and H2, had been found. The H2 lineage, representing the 900-kb inversion polymorphism, is found at a frequency of 20% in Europeans. For all 3 individuals, 1 of the parents carried the H2 haplotype. Parent-of-origin analysis showed that the deletion occurred on the H2 haplotype in 2 individuals, but was inconclusive in the third. The H2 haplotype differs from the H1 by a directly oriented low-copy repeat (LCR) that immediately flanked the breakpoints in all 3 individuals. This suggested that these deletions resulted from nonallelic homologous recombination, mediated by this H2-specific LCR.

Shaw-Smith et al. (2006) likewise described 3 individuals with a heterozygous 17q21.3 deletion detected by array CGH. In each case the parent-of-origin of the deleted chromosome 17 carried at least 1 H2 chromosome.

Approximately 5% of the human genome is composed of segmental duplications that are more than 1 kb long and show more than 90% sequence identity, the majority of which have an interspersed, rather than tandem, distribution (Bailey et al., 2002; Cheung et al., 2001). These duplication blocks act as substrates for nonallelic homologous recombination, leading to the deletion, duplication, or inversion of the intervening sequence (Stankiewicz and Lupski, 2002). Based on the duplication architecture of the genome, Sharp et al. (2006) investigated 130 regions that they hypothesized as candidates for previously undescribed genomic disorders. They tested 290 individuals with mental retardation by BAC array CGH and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in 4 individuals. By using oligonucleotide arrays, they refined the breakpoints of this microdeletion, defining a 478-kb critical region containing 6 genes that were deleted in all 4 individuals; they noted that 2 of these, CRHR1 and MAPT, are highly expressed in brain and have been implicated in neurodegenerative and behavioral phenotypes and are therefore excellent candidates for dosage-sensitive genes underlying this microdeletion syndrome.

Using high resolution oligonucleotide arrays to analyze 22 patients with 17q21.31 deletion syndrome, Koolen et al. (2008) narrowed the critical region to a 424-kb genomic segment encompassing at least 6 genes, including MAPT. Five deletion carriers had a greater than 500 bp rearrangement at the proximal breakpoint within an L2 LINE motif, suggesting a hotspot for nonallelic homologous recombination. In addition, every case examined showed that the parent originating the deletion carried the H2 haplotype, indicating that this inversion is a necessary factor for deletion to occur.

Cooper et al. (2011) compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. They identified the 17q21.31 deletion in 23 individuals and atypical deletions in 3 individuals. The smallest deletion refined the phenotype-associated critical region (Chr17:41,356,798-41,631,306, NCBI36) to encompass only 5 RefSeq genes.

Molecular Genetics

Among 11 patients with 17q21.31 deletion syndrome, Tan et al. (2009) found that the deletions ranged from 0.44 to 0.68 Mb in size, and included the CRHR1 (122561), MAPT (157140), IMP5 (608284),and STH (607067) genes, and part of the KIAA1267 gene (KANSL1; 612452).

By exome sequencing of a girl with classic features of chromosome 17q21.31 deletion syndrome who did not have a deletion on FISH or array CGH analysis, Zollino et al. (2012) identified a de novo heterozygous truncating mutation in the KANSL1 gene (612452.0001). Direct sequencing of this gene in another unrelated girl with features of the disorder in whom no deletion could be detected identified a second truncating mutation (612452.0002). The findings indicated that point mutation in the KANSL1 gene is sufficient for full manifestations of chromosome 17q21.31 deletion syndrome, and indicated that it is a monogenic disorder caused by haploinsufficiency of KANSL1.

By Sanger sequencing of the KANSL1 gene in 16 individuals with features of 17q21.31 deletion syndrome who did not have copy number variations in the MAPT or KANSL1 genes, Koolen et al. (2012) identified different de novo heterozygous truncating mutations in the KANSL1 gene (612452.0003 and 612452.0004) in 2 unrelated patients. Whole-transcriptome sequencing of 3 individuals with the classic 17q21.31 deletion showed that expression levels of KANSL1 were reduced by half. Whole-transcriptome sequencing of 1 of the patients with a point mutation showed differential expression of similar genes as those in patients with deletions; these genes are believed to be involved in neuronal/synaptic processes. The findings showed that haploinsufficiency of KANSL1 is sufficient to cause the classic 17q21.31 microdeletion syndrome phenotype, and provided evidence that the histone acetyltransferase complex may have a role in human cognitive function and developmental processes.

Itsara et al. (2012) used a combination of somatic cell hybrids, array comparative genomic hybridization, and the specificity of next-generation sequencing to determine breakpoints that occur within segmental duplications at the 17q21.31 locus in 3 deletion-bearing individuals. For 2 cases, Itsara et al. (2012) observed breakpoints consistent with nonallelic homologous recombination involving only H2 chromosomal haplotypes, as expected. Molecular resolution revealed that the breakpoints occurred at different locations within a 145-kb segment of greater than 99% identity and disrupted KANSL1. In the remaining case, they found that unequal crossover occurred interchromosomally between the H1 and H2 haplotypes and that this event was mediated by a homologous sequence that was once again missing from the human reference. Interestingly, the breakpoints mapped preferentially to gaps in the current reference genome assembly, which were resolved in this study.

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 17q21.31 deletion was identified in 22 cases and no controls for a p value of 2.49 x 10(-5) and a frequency of 1 in 716 cases.

Koolen et al. (2016) reported 45 patients with KDVS confirmed by genetic analysis, including 33 with a 17q21.21 microdeletion encompassing the KANSL1 gene and 12 with a de novo heterozygous mutation in KANSL1 (see, e.g., 612452.0004-612452.0006), all of which were predicted to result in haploinsufficiency. Functional studies of the variants were not performed. Koolen et al. (2016) noted that genetic testing of the 17q21.31 locus can be challenging because of the structural complexity of the genomic region.

Population Genetics

Koolen et al. (2008) estimated the prevalence of the syndrome to be 1 in 16,000 and suggested that it is currently underdiagnosed.

Evolution

The analysis of Zody et al. (2008) of the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism favored the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. The authors further showed that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.

Steinberg et al. (2012) investigated the genetic diversity of the 17q21.31 inversion polymorphism in 2,700 individuals, with an emphasis on African populations. Steinberg et al. (2012) characterized 8 structural haplotypes due to complex rearrangements that varied in size from 1.08 to 1.49 Mb and provided evidence for a 30-kb H1-H2 double recombination event. They showed that recurrent partial duplications of the KANSL1 gene (612452) have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. The authors identified a likely ancestral H2 haplotype (H2-prime) lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently in Europeans, either because of extraordinary genetic drift or selective sweeps.

Boettger et al. (2012) developed a population genetics approach to analyze complex genome structures and identified 9 segregating structural forms of 17q21.31. Both the H1 and H2 forms of the 17q21.31 inversion polymorphism contain independently derived, partial duplications of the KANSL1 gene; these duplications, which produce novel KANSL1 transcripts, have both recently risen to high allele frequencies (26% and 19%) in Europeans. An older H2 form lacking such a duplication is present at low frequency in European and central African hunter-gatherer populations.