6q+ Syndrome, Partial

Partial trisomy of the long arm of chromosome 6 syndrome is a rare chromosomal disorder with distinctive phenotypic expressivity, in which cytogenetic abnormalities are usually reported in infancy and childhood. Ultrasonographic findings on trisomy of the distal long arm of chromosome 6 in previous studies are limited.

A 32-year-old, gravida 6, para 1, pregnant woman who had 4 spontaneous abortions underwent a clinical ultrasound examination at 26 weeks of gestation.

Ultrasonographic findings were microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery. Cytogenetic and single-nucleotide polymorphism array analyses were performed to estimate genetic factors of this diagnosis by amniocentesis.

After genetic counseling, the patient and her husband opted to terminate the pregnancy.

Cytogenetic examination of the fetus showed the karyotype 46,XX,der(20)t(6;20)(q24;p13). The single-nucleotide polymorphism (SNP) array showed a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13.

Ultrasonographic findings of fetal abnormalities, including microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery, may be related to a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13. More ultrasonographic and genotype studies are required to extend the phenotypic characterization of partial trisomy 6q syndrome.

To analyze a girl with moderate mental retardation and speech and language disorders with cytogenetics technique and next-generation sequencing (NGS).

G-banding chromosome analysis was used to ascertain the karyotype of the child and her parents, and NGS was used for determining the size and origin of the abnormal chromosome fragment. Mate-pair and PCR were used to determine its parental origin.

The karyotype of the child was determined to be 46,XX,add(1)(q44)dn, while her parents were both normal. NGS revealed that the child has harbored a partial trisomy of 6q24.3-q27, and the breakpoint was mapped to at 6q24.3q27. In addition, a 2.5 Mb microdeletion at 1q44 was found in the patient.

No recognizable phenotype was associated with 1q44 deletion. The abnormal phenotypes presented by the child may be attributed to the 6q24.3-q27 triplication. Compared with conventional cytogenetic analysis, NGS has a much higher resolution and great accuracy.

Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known.

We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members.

Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.