Sharanbeer Kaur, Gregory Peters, Dale Wright
Sydney Genome Diagnostics, The Children’s Hospital Westmead, NSW, 2145
The recurrent 3q13.2q31.31 microdeletion has been associated with a rare but emerging syndrome with clinical features overlapping Primrose syndrome. Herein, two cases are described.
Case 1: 9 year old female with moderate global delay. Case 2: 4 year old female with global development delay (motor and language), macrocephaly and ‘distinctive appearance’. CGH microarray was performed using an 8x60K ISCA design (Agilent Technologies), and data analysed using the ADM-2 algorithm with copy number abnormalities (CNA) calls based on five consecutive probes (Cytogenomics v18.104.22.168). UCSC genome browser [hg19] was used to evaluate CNA pathogenicity and segmental duplications >1000bp. Parental follow-up studies were requested to investigate inheritance.
Case 1 and 2 both showed heterozygous deletions [~3.31Mb] within chromosome band 3q13.2q13.31, extending from coordinates 112.18Mb to 115.49Mb. This included 29 genes, from BTLA to GAP43. Two of the 29 genes are associated with OMIM-listed disease; DRD3 and ZBTB20. No flanking segmental duplications were identified. Parental studies for Case 2 were negative, indicating a de novo mutation. Parental samples for Case 1 have not been received.
The recurrent 3q13.2q13.31 deletion was identified in two cases. Case 2 was de novo and Case 1 of unknown inheritance. Clinical features of the emerging syndrome include development delay, hypotonia, high-arched palate, increased occipitofrontal circumference and distinctive facial features; short philtrum and protruding lips. A smallest region of overlap has been defined as ~0.6Mb, which includes five genes: DRD3, ZNF80, TIGIT, MIR568 and ZBTB20. Primrose syndrome is caused by heterozygous mutations in ZBTB20. DRD3 is associated with schizophrenia. Both are considered candidate genes with respect to development delay, psychiatric features, and associated structural brain malformations. Recurrent deletions typically arise via non-homologous allelic recombination facilitated by flanking segmental duplications, however none were identified >1000bp. This may suggest involvement of smaller duplicated segments, or an alternative mechanism.
I am a Trainee Hospital Scientist at the Children’s Hospital Westmead under the Sydney Genome Diagnostics Program.