Investigation of selected genomic deletions and duplications in a cohort of 338 patients presenting with syndromic obesity by multiplex ligation-dependent probe amplification using synthetic probes

D’Angelo, Carla S; Varela, Monica C; de Castro, Cláudia IE; Kim, Chong A; Bertola, Débora R; Lourenço, Charles M; Perez, Ana Beatriz A; Koiffmann, Celia P

doi:10.1186/s13039-014-0075-6

Molecular Cytogenetics

Table 1 Chromosomal aberrations detected primarily by the MLPA testing panels

From: Investigation of selected genomic deletions and duplications in a cohort of 338 patients presenting with syndromic obesity by multiplex ligation-dependent probe amplification using synthetic probes

Case	Cytoband	CNV type	Aberrant MLPA probe(s)	CMA/ MLPA	Genomic coordinates	Size (Mb)	Inheritance	Phenotype
P1	1q21.1	Gain	PRKAB2, ACP6	180 K oligoarray	chr1:146.07-147.83 Mb	1.8	n.d.	6.8 yr old male (BMI >95^th), speech delay (>2 yr), macrocephaly (>98^th), accelerated growth (90-95^th), genital hypoplasia
P2	2q37.1q37.2	Gain	--	500 K SNP array	chr2:235.09-236.8 Mb	1.7	--	11 yr old male (BMI >95^th), DD (walked: 3.6 yr, spoke: 3 yr); ID, hypotonia, motor and speech impairment, hyperphagia, seizures, macrocephaly (98^th), facial dysmorphisms, inverted nipples, unilateral cryptorchidism
P2	2q37.2q37.3	Loss	HDAC4, GPR35	500 K SNP array	chr2:236.94-243.01 Mb	6.1	de novo
P3	2q37.2q37.3	Loss	HDAC4, GPR35	60 K oligoarray	chr2:236.85-243.0 Mb	6.2	n.d.	21 yr old male; DD, hypotonia, hyperphagia, obesity, absent speech, mild dysmorphisms, supernumerary teeth, unilateral cryptorchidism, micropenis
P4	2q37.2q37.3	Loss	HDAC4, GPR35	60 K oligoarray	chr2:237.22-243.0 Mb	5.8	de novo	8 yr old female (BMI >95^th), DD (walked: 17mo, spoke: >2 yr), learning disability, dolichocephaly, facial dysmorphisms, mamilar hypertelorism, inverted nipples, brachydactyly, 2–3 toe syndactyly, hirsutism, joint hypermobility
P5	2q37.3	Loss	GPR35	180 K oligoarray	chr2:240.88-243.03 Mb	2.2	n.d.	5 yr old female (BMI >95^th), DD (walked: 2 yr, spoke: 3 yr), ID, behavior problems, prominent ear, thin elongated eyebrow, strabismus
P5	17q25.3	Gain	--	180 K oligoarray	chr17:78.77-81.06 Mb	2.3	n.d.
P6	9q34.3	Loss	EHMT1	60 K oligoarray	chr9:140.67-141.02 Mb	0.4	de novo	9.5 yr old female (BMI >95^th), DD (walked: 18mo, spoke: 6 yr), hypotonia, hyperphagia, behavior problems, tall stature (>97^th)
P7	16p11.2	Loss	SH2B1	180 K and 60 K oligoarray	chr16:28.82-29.04 Mb	0.2	de novo	7 yr old female (BMI >95^th), GDD, hypotonia, ADHD, hyperphagia, speech impairment, deep-set eyes, straight eyebrows, thick earlobe
P8	16p11.2	Gain	CDIPT, MAPK3	180 K and 60 K oligoarray	chr16:29.65-30.19 Mb	0.5	paternal	8.5 yr old male, GDD, hyperphagia, obesity [sic], speech impairment, behavior problems, scoliosis
P9	17p11.2	Loss	FLCN,¹ RAI1	P064 kit	chr17:17.13-19.29 Mb	2.2	de novo	11 yr old male (BMI >95^th), DD, ID, hyperphagia, behavior and sleep problems, macrocephaly (>98^th), typical facial dysmorphisms, brachydactyly, 2–3 toe syndactyly, micropenis
P10	17p11.2	Loss	FLCN,¹ RAI1	P064 kit	chr17:16.85-19.29 Mb	2.4	de novo	10 yr old male (BMI >95^th), DD, ID, hypotonia, hyperphagia, behavior and sleep problems, speech and hearing impairment, facial dysmorphism
P11	17p11.2	Loss	FLCN,¹ RAI1	P064 kit	chr17:16.85-19.29 Mb	2.4	de novo	7 yr old female (BMI >95^th), DD (walked: 2 yr, spoke: 5 yr), ID, behavior problems, myopia, strabismus, astigmatisms, hypoplasia genital, 2–3 toe syndactyly
P12	17p11.2	Loss	FLCN,¹ RAI1	P064 kit	chr17:16.85-19.29 Mb	2.4	n.d.	6.8 yr old male (BMI >95^th), DD (walked: 5 yr, spoke: >4 yr), hypotonia, hyperphagia, compulsive behavior, typical facial dysmorphisms
P13	22q11.21	Loss	CRKL	P023 kit	chr22:19.32-21.35 Mb	2.0	de novo	3 yr old male (weight >97^th), GDD, absent speech, hypotonia, mild facial dysmorphism
P14	22q11.21	Loss	CRKL	P023 kit	chr22:19.32-21.35 Mb	2.0	de novo	9 yr old male (BMI >95^th), ID, hypotonia, speech delay (>3 yr), behavior problems, ADHD, hyperphagia, accelerated growth (90-95^th), hypogonadism
P15	22q11.21	Loss	CRKL	P023 kit	chr22:19.32-21.35 Mb	2.0	paternal	13mo old male (BMI 76^th), DD, hypotonia, growth delay (3^rd-5^th), relative overweight (weight to height ratio >75th percentile), dolichocephaly, facial dysmorphisms
P16	22q11.21	Gain	CRKL	P023 kit	chr22:19.32-21.35 Mb	2.0	paternal	8.6 yr old male (weight >97^th), DD (walked: >2 yr), mild ID, hypotonia, facial dysmorphisms, widened mediastinum, brachydactyly, micropenis
P17	22q11.22q11.23	Loss	RAB36	180 K oligoarray	chr22:23.01-23.65 Mb	0.6	maternal	2.8 yr old female (BMI 85^th), hypotonia, non-ambulatory and non-verbal, epilepsy (onset at 3mo), brachycephaly, deep-set eyes, visual impairment, joint laxity
P18	22q11.22q11.23	Loss	RAB36	500 K SNP array	chr22:23.06-23.7 Mb	0.6	n.d.²	15 yr old male (BMI >95^th), GDD, ID, hypotonia, absent speech, behavioral and sleep problems, facial dysmorphisms, strabismus, hyperprolactinemia, micropenis

Breakpoints based on the coordinates of the first and last altered array probes. The alterations of patients 9–12 and 13–16 were fine-mapped by additional MLPA probes in the commercial kits P064-B2 and P023-B, respectively. Probes in the MLPA kit P064-B2 covering the 17p11.2 region are TNFRSF13B, LRRC48, LLGL1, PRPSAP2 and MFAP4. Probes in the MLPA kit P023-B covering the 22q11 region are IL17R, BID, HIRA, CLDN5, KIAA1652, KLHL22, PCQAP, SNAP29, LZTR1 and MIF.
¹The FLCN probe is included in the MLPA P200 and P300 reference kits. It is located within the SMS region on chromosome 17p11.2, and was found deleted in all patients with deletions in RAI1. ²Adopted child. Not determined (n.d.); years (yr); months (mo). ID, intellectual disability; DD, developmental delay; GDD, global DD; ADHD, attention-deficit hyperactivity disorder.

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