Chromosome 15q25 Deletion Syndrome

A number sign (#) is used with this entry because the phenotype is a contiguous gene syndrome caused by deletion on chromosome 15q25.2-q25.3.

Clinical Features

By array-CGH testing of over 12,000 patients referred for various congenital abnormalities, Wat et al. (2010) identified 3 boys with a de novo heterozygous deletion of chromosome 15q25.2. Two of the boys, aged 1 month and 13 years, had congenital diaphragmatic hernia (DIH); there were 20 patients with DIH in the entire cohort. The older boy had global developmental delay, thin body habitus, pectus excavatum, and unilateral cryptorchidism, whereas the infant had cardiac ventricular septal defects, small corpus callosum and underdeveloped gyri, inguinal hernia, and bilateral cryptorchidism. The third boy was 16 month of age and had dysmorphic facial features, cleft palate, and mild features of Diamond-Blackfan anemia (DBA, see 105650). A literature review identified 2 additional unrelated patients with a similar deletion of 15q25.2: one had DIH and the other had poor growth, mildly delayed psychomotor development, and anemia. Wat et al. (2010) noted that the DBA4 (612527)-associated gene RPS17 (180472) lies within the deleted region.

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. Among the cases, 6 (including 2 brothers) were identified as having a 15q25.2-q25.3 deletion. Clinical aspects of the probands were variable and consisted of neurologic features and developmental delay. One female had only mild motor delay associated with a congenital myopathy but was otherwise cognitively normal. This proband had inherited the deletion from her mother, whose only health complaint was migraines. The 2 brothers with the deletion had autism spectrum disorders. Developmental delay was reported in 3 of the 5, and seizure in 1.

Palumbo et al. (2012) reported a 9-year-old girl with delayed psychomotor development and complex behavioral abnormalities, including anxiety, hyperactivity, autistic features, attention deficits, and oppositional behavior associated with a de novo heterozygous 1.6-Mb deletion of 15q25.2. Additional features included generalized hypotonia, long fingers, pectus excavatum, scoliosis, and facial dysmorphism with high hairline, round eyes, flat nasal bridge, thin upper vermilion border, and dental abnormalities. Palumbo et al. (2012) noted the deletion of several genes within this region that may contribute to the phenotype, including ADAMTSL3 (609199) and MIR4115.

Doelken et al. (2013) reported 2 unrelated males with microdeletions of chromosome 15q25.2. One patient was a 17-year-old boy with a 2.51-Mb deletion of 15q25.2 and a 2.52-Mb duplication of 15q24.2. He had mild intellectual disability, iron deficiency anemia, portal vein thrombosis, inguinal hernia, brachydactyly, short stature, and dysmorphic features, including myopathic facies, ptosis, and downward slanting palpebral fissures. Neither the deletion nor the duplication was present in the unaffected father; a maternal sample was not available for testing. The other patient was a 17-month-old boy with severely delayed psychomotor development, seizures, hypotonia, microcephaly, and dysmorphic features who had a 604-kb deletion of 15q25.2 inherited from his unaffected father, a 2.5-Mb deletion of 1q21.1 inherited from his unaffected mother, and a de novo 172-kb deletion of Xq12 affecting the OPHN1 gene (300127), which is known to be involved in intellectual disability (300486).

Burgess et al. (2014) reported 4 additional unrelated children between 5 months and 5 years of age with different de novo heterozygous deletions of chromosome 15q25.2. The deletions ranged in size from 1.5 to 6.7 Mb; 1 patient also had a 0.6-Mb deletion of 16p11.2, which is known to contribute to a neurobehavioral phenotype (611913). Three patients were confirmed to have a heterozygous deletion of RPS17L (see 180472) and HOMER2 (604799). Common clinical features included delayed development, short stature, and variable dysmorphic facial features. Three had macrocytic anemia, 3 had cardiac defects, including 1 with dextrocardia, and 2 had thromboses, including 1 with portal thrombosis. Additional variable features included inguinal hernia, cryptorchidism, obstructive sleep apnea, and cleft lip.

Cytogenetics

Cooper et al. (2011) identified 6 children among 15,767 children with intellectual disability and various congenital defects who had a similar deletion in 15q25.2-q25.3. Five (2 of whom were brothers) of these carried a 660-kb deletion (chr15:82,889,423-83,552,890, NCBI36) flanked by segmental duplications (69.8 kb, 98.6% identity). This microdeletion maps within a genomic hotspot flanked by high identity segmental duplication blocks (69.8 kb, 98.6% identity). The directly oriented segmental duplications likely mediate the underlying 15q25 rearrangements by nonallelic homologous duplication.