Haploinsufficiency ofANO6, NELL2andDBX2in a boy with intellectual disability and growth delay

Abstract

We report on a 10-year-old-boy presenting with moderate intellectual disability (ID), impaired motor skills, hypotonia, growth delay, minor anomalies, misaligned teeth, pectus excavatum, small hands and feet, widely spaced nipples, and a 1.13 Mb de novo deletion on HSA12q12 (chr12:44,830,147-45,964,945 bp, hg19), deleting ANO6, NELL2, and DBX2 and the pseudogenes PLEKHA8P1 and RACGAP1P. We suggest DBX2 and NELL2 as disease-causing genes and their haploinsufficiency to be involved in the psychomotor delay in the patient. DBX2 encodes a homeobox protein, highly expressed during neuronal development and regulating differentiation of interneurons in brain and spinal cord. NELL2 is expressed in most of the central and peripheral nervous system, with highest expression in hippocampus and cerebellum, maximizing during neuronal differentiation. The deletion in our patient is the smallest in HSA12q12 reported to date, and it is included in the deletion carried by four previously reported patients. The clinical presentation of these patients points to the recurrence of the following manifestation, possibly delineating a 12q12 deletion syndrome phenotype: moderate to severe developmental/intellectual delay, hypotonia, postnatal growth retardation, skeletal and dental anomalies, minor facial anomalies including strabismus, down slanting palpebral fissures, and large/low-set ears.

Proximal Deletion 12q with a New Insight to Growth Retardation

“…The deleted region in our patient partially overlaps with previously described deletions in 5 independent cases ( Fig. 2 ) [Tonoki et al, 1998;Miyake et al, 2004;Failla et al, 2008;Carlsen et al, 2015;Weng et al, 2018]. Four cases, including our patient, presented with psychomotor developmental delay, short stature, decreased head circumferences, as well as large low-set ears, strabismus, broad nasal bridges and/or noses, long philtrums, downturned corners of the mouth, and widely spaced nipples ( Table 1 ).…”

“…Four cases, including our patient, presented with psychomotor developmental delay, short stature, decreased head circumferences, as well as large low-set ears, strabismus, broad nasal bridges and/or noses, long philtrums, downturned corners of the mouth, and widely spaced nipples ( Table 1 ). The patient described by Carlsen et al [2015] showed most of the above-mentioned clinical features, although he had small ears, a wide mouth and rather an increased head circumference. At a clinical investigation at age 10 years, his height and weight were within the normal range (10th centile).…”

“…other patients. Moreover, congenital atrial septal defect was present in one patient reported by Weng et al [2018], and a dilated aortic root and a slightly thickened ventricular septum were detected in one patient at age 21 month reported by Carlsen et al [2015].…”

“…Proximal deletions of the long arm of chromosome 12 have been described in about 20 patients. Five of these share a well-defined phenotype characterised by developmental delay with cognitive impairment, growth retardation, and decreased head circumference as well as a broad forehead, large low-set ears, broad nasal bridge and/or nose, long philtrum, and widely spaced nipples [Tonoki et al, 1998;Miyake et al, 2004;Failla et al, 2008;Carlsen et al, 2015;Weng et al, 2018]. All these patients have an overlapping deleted region at 12q12, where YAF2 , AMIGO2 and NELL2 were suggested as candidate genes for growth and psychomotor retardation.…”

Deletion at 12q12 increases the risk of developmental delay and intellectual disability

“…These findings suggest that NELL2 and either TWF1 or TMEM117 play roles in development. NELL2 mRNA levels were also found to be decreased in patient 2 (Carlsen et al., 2015). Certain genes in 12q12 have the same development‐related functions.…”