190‐kb duplication in 1p36.11 including PIGV and ARID1A genes in a girl with intellectual disability and hexadactyly

To the Editor : Coffin–Siris syndrome (CSS) is a rare autosomal dominant syndrome characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features and hypoplastic nail of the fifth finger and/or toe (1). Germline mutations in ARID1A, one of the SWItch/Sucrose NonFermenting complex subunit genes, were recently identified in about 90% of CSS patients (2). Hyperphosphatasia mental retardation syndrome (HPMR), also known as Mabry syndrome, is an autosomal recessive syndrome which was first related to the triad: developmental disability, seizures and hyperphosphatasia manifesting in the first year of life (3). Within this broad phenotype, Thompson et al. delineated a specific clinical entity characterized by facial gestalt including long palpebral fissures, a broad nasal bridge and tip, a tented mouth, and brachytelephalangy (4). Homozygous and compound heterozygous missense mutations in PIGV , the first gene associated with Mabry syndrome and encoding the second mannosyltransferase in the GPI-anchor biosynthesis pathway, were identified using wholeexome sequencing in HPMR families (5). Here, we report for the first time, the clinical and molecular characterization of a patient with de novo 1p36.11 microduplication including PIGV and ARID1A. The propositus is a girl born at 41 weeks after a normal delivery from non-consanguineous healthy parents with no family history of congenital anomalies or developmental delay. Prenatal ultrasonography performed in the 22nd week of gestation had revealed a four-limb postaxial hexadactyly. The supernumerary digits were removed by surgery at 4 months (Fig. 1a,b). Her birth weight was 3180 g (> −1 SD), length 46 cm (−2 SD), and head circumference 33 cm (−1 SD). To date (3 years), her height is 87 cm (−2 SD), weight 11 kg (−2 SD), and head circumference 44 cm (< −2 SD). At 9 months old, she presented repetitive and stereotyped upper limbs movements (see Video S1, Supporting information). She had facial dysmorphic features including broad nasal bridge and tip, short philtrum, thin upper lip, abnormal ears, spare scalp hairs (Fig. 1c,d) associated with severe microcephaly of prenatal onset and overlapping toes (Fig. 1b). She also suffered of constipation, gastro-oesophageal reflux, feeding problems and eczema in relation to a cow’s milk protein allergy. She had motor skills delay with no sign of walking or crawling at 36 months. The sitting position was acquired at the age of 12 months. She had severe developmental and speech delay with only two words at 2 years old. Complete clinical and radiological examinations showed no specific abnormalities at the age of 3. Serum alkaline phosphatase level was normal (180 IU/l). No lysosomal storage and intracellular inclusions in cultured fibroblasts were observed after periodic acid Schiff reaction like those reported in the Mabry syndrome (6). It is notable that a duplication in PIGV – one of genes inactivated in Mabry syndrome – does not result in alterations in alkaline phosphatase activity in 1p36.11 duplication syndrome. Array comparative genomic hybridization analyses (CGH Microarray Kit 180K, Agilent, CA) showed a 190-kb duplication in 1p36.11 extending from base 27,001,256 to 27,190,935 (NCBI, hg 19) from the 1p telomere (Fig. 1e). No other abnormalities larger than three probes were observed, excluding well-known benign copy number variation reported in the Database of Genomic Variants (DGV). Custom multiplex ligation-dependent probe amplification (MLPA) analysis confirmed the duplication in the patient (Fig. 1f) and analysis of the parents revealed normal MLPA profiles. The fluorescent in situ hybridization analysis showed the tandem duplication in the 1p36.11 region (Fig. 1g). Reverse transcriptase multiplex ligation-dependent probe amplification analysis of mRNAs in fibroblast cell revealed that expression of ARID1A and PIGV was respectively about 1.5and 3-fold higher compared to controls (Fig. 1h). In this de novo 190-kb duplicated region, four known protein-coding genes are listed in NCBI build 37.2. Among them, ARID1A, PIGV , ZDHHC18 , SFN are completely duplicated. ZDHHC18 , whose function is unknown, is expressed predominantly in lymphoid tissue. SFN encodes for the stratifin involved in multiple cellular processes and commonly silenced in various cancers (7). In DGV, variation 4218 described many copy number variations including ZDHHC18 and SFN , suggesting that ZDHHC18 and SFN duplications are likely benign, although we cannot formally exclude their contribution in the phenotype.