Genotype-phenotype relationship in three cases with overlapping 19p13.12 microdeletions

Abstract

We describe the detailed clinical and molecular characterization of three patients (aged 7, 8(4/12) and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

Figure 1

Photographs of case 1 at the age of 6 months (a), 8 years (b) and 17 years (c), and frontal (d) and lateral (e) view at the age of 31 years. Note the brachycephaly (a, d, e), tall forehead (a, c, d), ptosis (a–c), anteverted nares (a–d), long philtrum (a–d), thin upper lip (a–e), synophrys (a–d), short neck (c), anteverted ears (a, c, d) with thin helices (e) as well as symmetrically arranged, vaguely outlined nodules and partly confluent plaques accompanied by a fuzzy erythema on the forehead at age 31 years (d, e).

Figure 2

Photographs of case 3 at the age of 7 years, frontal (a, c) and lateral (b) view. Note the tall forehead, anteverted nares, thin upper lip, anteverted ears and long philtrum.

Figure 3

Molecular characterization of the deletions. (a) Map of the 19p13.12–p13.13 region; the deletions are represented by black bars, and the region of overlap between the deletions is shaded in gray. Only the genes discussed in the text are shown. According to the Database of Genomic Variants (projects.tcag.ca/variation), several copy-number variations (CNVs), mostly deletions, are found in the 19p13.12–p13.13 regions. Although some of them (no. 50073, 50074 and 10543) may be extremely rare CNVs, others, including no. 5089 and 5090 in the SRO region, have been detected at very high frequency exclusively in one report using BAC-array analysis, and may therefore be somewhat unreliable. (b) Aligned aCGH profile details of the deletions; the deleted regions are shaded in gray. (c) Sequence alignment of the breakpoint junctions; the 3-bp microhomology in case 1 and informative mismatching bases in cases 2 and 3 are shown in bold.