A number sign (#) is used with this entry because of evidence that Witteveen-Kolk syndrome (WITKOS) is caused by heterozygous mutation in the SIN3A gene (607776) on chromosome 15q24.

Some patients with a similar disorder have a contiguous gene deletion syndrome (chr15:72.15-73.85 Mb, NCBI36) or a contiguous gene duplication syndrome that include the SIN3A gene.

Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by Balasubramanian et al., 2021).

Witteveen et al. (2016) reported 6 patients from 2 unrelated families and 3 singleton patients with intellectual disability and common dysmorphic facial features. Most of the patients were children, ranging in age from 4 to 16 years, but there was a mildly affected parent in each of the 2 families. The patients had mild intellectual disability with delayed development and speech delay, although some had normal motor and speech development. Several had autistic behavior and 2 had well-controlled seizures. Dysmorphic features included broad forehead, long face, downslanting palpebral fissures, flat or depressed nasal bridge, large fleshy ears, long and smooth philtrum, small mouth, and pointed chin. Additional variable features included short stature, microcephaly, joint hypermotility, and small hands and feet. Brain imaging showed dilated ventricles, thin corpus callosum and, in some cases, dysgyria or polymicrogyria.

Narumi-Kishimoto et al. (2019) reported a 7-year-old Japanese girl with a SIN3A mutation who was diagnosed with speech delay at 3 years of age. At age 5 years, she was diagnosed with intellectual disability, autism spectrum disorder, and poor motor coordination. At age 6 years and 7 months, she had normal height, weight, and head circumference. Facial features included a long face, depressed nasal bridge, and downslanting palpebral fissures. She had small hands and fifth finger clinodactyly.

Balasubramanian et al. (2021) reported clinical features in 28 patients, aged 0.6 to 67 years (average, 8.2 years), with mutation in the SIN3A gene. Fifteen of the patients had global developmental delay. Of 16 patients aged 8 years and older, 7 had mild intellectual disability, 4 had moderate intellectual disability, 1 had severe intellectual disability, and 4 did not have cognitive impairment. Three of 23 patients aged 2 years and older were diagnosed with autism spectrum disorder, and 4 patients were diagnosed with attention deficit-hyperactivity disorder (ADHD). Thirteen patients had small head size, 8 patients had low weight, and 5 patients had short stature. Fifteen patients had feeding difficulties. Fourteen patients were reported to have facial dysmorphism, including a broad and tall forehead, small mouth, thin upper lip, and downslanting palpebral fissures. Of 9 patients who had brain imaging, ventriculomegaly was seen in 2, hypoplastic/dysplastic corpus callosum was seen in 2, cerebellar atrophy was identified in 2, and Chiari 1 malformation was seen in 1.

Chromosome 15q24 Deletion Syndrome

Formiga et al. (1988) reported 2 unrelated patients with an interstitial deletion of chromosome 15q. The first child showed intrauterine and postnatal growth retardation, severe psychomotor retardation, and dysmorphic facial features, including microcephaly, slight microphthalmia, hypertelorism, slanting palpebral fissures, epicanthal folds, strabismus, hypopigmented irides, short nose, microretrognathia with open mouth and high-arched palate, and large ears. She also had abnormal insertion of several toes. Karyotype analysis showed a deletion of chromosome 15q22-q25. The second child had severe psychomotor retardation, hypotonia, and similar facial dysmorphism with small, slanting palpebral fissures, microphthalmia, large ears, hypopigmented irides, and microretrognathia with open mouth and arched palate. She had clinodactyly, abnormal insertion of the toes, and cardiovascular abnormalities, consisting of septal hypertrophy with dilatation of the aorta and pulmonary artery. Karyotype analysis showed a deletion of chromosome 15q21-q24.

Bettelheim et al. (1998) reported 2 unrelated fetuses with significant left-sided congenital diaphragmatic hernia detected by ultrasound. One died in utero, and the other died 10 minutes after birth. Karyotype analysis showed a de novo interstitial deletion of chromosome 15q24 in the first and a deletion of chromosome 15q24-qter in the second.

Cushman et al. (2005) reported 3 patients with interstitial deletions involving chromosome 15q24, including 2 with cryptic deletions and 1 with a cytogenetically visible deletion of chromosome 15q22.3-q24. All had global developmental delay and hypotonia. The 2 males had hypogonadism. Two patients were reported to have dysmorphic facial features, including epicanthal folds, strabismus, micrognathia, and cupped or notched ears, as well as digital anomalies, such as clinodactyly and tapering of the fingers.

Sharp et al. (2007) reported 4 unrelated boys with mild to moderate developmental delay and dysmorphic facial features who were each heterozygous for a deletion at chromosome 15q24. Three had low birth weight, short stature, and microcephaly. Dysmorphic features included high anterior hairline, hypertelorism, downslanting palpebral fissures, broadening of the medial eyebrows, broad nasal base with flaring of the alae nasi, long smooth philtrum, and full lower lip. Three had joint laxity, 2 had scoliosis, and 3 had hypospadias. All had digital anomalies, such as long slender fingers and proximally implanted thumbs. Two had growth hormone deficiency; the other 2 were not tested.

Van Esch et al. (2009) reported a 33-year-old man with severe mental retardation and a chromosome 15q24 microdeletion. Hypertelorism, broad nasal bridge, and large ears were noted in infancy. He had delayed psychomotor development and hypotonia. As a child, he had hyperactive behavior and showed aggressive outbursts, requiring institutionalization. At age 33, he was found to have a congenital diaphragmatic hernia of the Morgagni type. Dysmorphic features at that time included obesity, strabismus, downslanting palpebral fissures, long face with high forehead, long philtrum, and high-arched palate. He also had small genitals and unilateral cryptorchidism. Cytogenetic and array CGH analysis detected a de novo 3.1-Mb deletion at chromosome 15q24 with breakpoints within segmental duplication clusters.

El-Hattab et al. (2009) reported 4 patients with the 15q24 deletion syndrome. All had developmental delay, short stature, hypotonia, joint laxity, digital anomalies, and characteristic facial features similar to previously reported cases. In a review of common reported features, El-Hattab et al. (2009) concluded that 15q24 deletion represents a distinct syndrome. General features include mild to severe developmental delay, hypotonia, short stature, digital anomalies, joint laxity, genital anomalies, and characteristic facial features, such as a high anterior hairline, facial asymmetry, ear malformations, broad medial eyebrows, downslanted palpebral fissures, hypertelorism, epicanthal folds, strabismus, long smooth philtrum, full lower lip, and broad nasal base. The distal extremity malformations consist of thumb anomalies, small hands with brachydactyly, clinodactyly, and foot-ankle deformities.

Witteveen et al. (2016) identified 4 new patients with de novo heterozygous 15q24 deletions associated with intellectual disability and dysmorphic facial features. Brain imaging, performed on 2 patients, showed cortical dysgenesis, thin corpus callosum, and decreased white matter/delayed myelination. One had autism spectrum disorder and another had seizures. The smallest region of overlap of the deletion was about 200 kb and included the SIN3A gene.

Chromosome 15q24 Duplication Syndrome

Kiholm Lund et al. (2008) reported a 2-year-old boy with a chromosome 15q24 microduplication that was reciprocal to the minimal critical region for the chromosome 15q24 microdeletion. He had global developmental delay, hypospadias, and dysmorphic features, including low-set, posteriorly rotated ears, broad nasal bridge, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick upper lip, and smooth philtrum. He also had digital anomalies with overlapping fingers and hypoplastic nails and hypotonia. Although the duplication was inherited from the healthy father, it was considered clinically significant, since the phenotype in the proband resembled the reciprocal deletion syndrome.

El-Hattab et al. (2009) reported a 15-year-old boy with short stature, mild mental retardation, hypertonia, attention-deficit hyperactivity disorder, and Asperger syndrome who had a 2.6-Mb microduplication of chromosome 15q24, including the 1.75-Mb critical region. He had a long face, epicanthal folds, downslanting palpebral fissures, high nasal bridge, smooth philtrum, and full lower lip. Two sibs from a second family had a 2.11-Mb duplication of chromosome 15q24, distal to the critical region, and they showed developmental delay, axial hypotonia, tapering fingers, and characteristic facial features, such as hypertelorism, flat nasal bridge, and prominent ears. The 2 sibs inherited the duplication from their mother, who had learning disabilities.

Coenen-van der Spek et al. (2023) identified a characteristic methylation profile in peripheral blood of patients with Witteveen-Kolk syndrome. The profile was first established in a training cohort of 14 patients with WITKOS and heterozygous mutations in the SIN3A gene. The patient profile was hypomethylated compared to controls. The profile was then evaluated in an additional 4 patients with WITKOS as an investigational cohort. These 4 patients were relatives of patients who were included in the training cohort but had milder overall phenotypes. The characteristic WITKOS methylation profile was also seen in this investigational cohort, indicating that the WITKOS episignature was detectable in patients with milder phenotypes as well as in those with more severe phenotypes.

By high-resolution oligonucleotide array analysis of 4 unrelated patients with 15q24 deletions ranging from 1.7 to 3.9 Mb in size, Sharp et al. (2007) found that the proximal breakpoints of 3 patients mapped to a common region, designated BP1. Two of these cases also shared a common distal breakpoint, BP3, with an alternate distal breakpoint in the third case, BP2. All of these breakpoints occurred in highly identical segmental duplication clusters. The fourth patient had an atypical deletion with unique breakpoints that occurred in nonrepetitive sequences. The minimal deletion critical region was 1.7 Mb between BP1 and BP2. In the 3 cases tested, the deletions were de novo on the maternal chromosome. Nonallelic homologous recombination (NAHR) was proposed as the molecular mechanism.

In a patient with the 15q24 deletion syndrome, Van Esch et al. (2009) found that the proximal breakpoint mapped to a low-copy repeat (LCR) region proximal to BP1 as defined by Sharp et al. (2007) and that the distal breakpoint coincided with BP2. Van Esch et al. (2009) commented that both their patient and a patient reported by Sharp et al. (2007) with diaphragmatic hernia had deletions extending toward the centromere and covering almost the entire 15q24.1 cytogenetic band. El-Hattab et al. (2009) reported 2 patients with more proximal breakpoints similar to the patients of Van Esch et al. (2009) and Sharp et al. (2007), but congenital diaphragmatic hernia was not reported.

El-Hattab et al. (2009) identified 2 new LCR clusters involved in 15q24 deletion syndrome in addition to the 3 reported by Sharp et al. (2007) and designated them as LCR15q24A and LCR15q24C. BP1, BP2, and BP3 were designated as LCR15q24B, LCR15q24D, and LCR15q24E, respectively. All the deletion and duplication breakpoints identified in their 7 patients were shown to map to these LCR regions. All 4 patients with the chromosome 15q24 deletion shared the 1.7-Mb critical region identified by Sharp et al. (2007). A microduplication found in 1 patient by El-Hattab et al. (2009) also included the 1.7-Mb critical region, but another microduplication in 2 sibs was distal to the critical region. Overall, the findings suggested that NAHR is the mechanism of the chromosome 15q24 deletion/duplication.

In 6 patients from 2 unrelated families and in 3 unrelated singleton patients with WITKOS, Witteveen et al. (2016) identified 5 different heterozygous truncating mutations in the SIN3A gene (607776.0001-607776.0005). The mutations, which were found by exome sequencing, were predicted to result in haploinsufficiency. The phenotype was similar to that observed in patients with chromosome 15q24 deletion syndrome, suggesting that haploinsufficiency for SIN3A is the main cause of the phenotype of that disorder.

By whole-exome sequencing in a Japanese girl with WITKOS, Narumi-Kishimoto et al. (2019) identified a de novo heterozygous duplication in the SIN3A gene (607776.0006).

In 28 individuals with WITKOS, Balasubramanian et al. (2021) identified heterozygous mutations in the SIN3A gene. Twenty-seven patients had a novel mutation, and 1 patient had a previously identified mutation (R1104X; 607776.0005). Twenty-five of the mutations were truncating and predicted to cause loss of function, 3 were missense mutations (A126V, K155E, M1106T), and 1 was a large in-frame gain including exons 10 through 12. The missense and in-frame gain mutations were not present in the gnomAD database. Twenty-six of the mutations were de novo, 1 was inherited from the patient's mother, and 1 had unknown inheritance.

Witteveen et al. (2016) found that knockdown of Sin3a using shRNA in mice resulted in a significant reduction of cortical progenitor neurons in the proliferative zone. Loss of Sin3a also caused a change in neuronal identity, suggesting that it is required for proper differentiation, and caused aberrant corticocortical projections with abnormal callosal axon elongation and deviation compared to controls. The findings were consistent with a critical role for Sin3a in regulating the development of the mammalian cerebral cortex.