A novel familial 9q31.2q32 microdeletion: Muscle cramping, somnolence, fatigue, sensorineural hearing loss, pubertal delay, and short stature

Abstract

Key Clinical Message We report a novel 9q31.2q32 (chr9: 109195179‐113974353, hg 18) microdeletion characterized by fatigue, muscle cramps, short stature, delayed puberty, sensorineural hearing loss, and mild developmental delay. Overlapping microdeletions reported in this region also demonstrate facial dysmorphism, skeletal anomalies, cleft palate, and cardiac valvular abnormalities. In comparing these cases, we suggest critical region of chr9: 109711873‐113407621 (hg 18).

Kallmann syndrome in a patient with Weiss–Kruszka syndrome and a de novo deletion in 9q31.2

“…KS-related phenotypes in our proband and representative previously reported patients with 9q31.2 deletions are shown in Fig.2and Supplementary Table2. There are two previous deletions that overlap with the one encountered in our proband, and are associated with delayed puberty or CHH(11,15).Ramineni et al reported a family, in which a deletion in 9q31.2 segregated with delayed puberty. The overlapping region between their deletion and that of ours encompassed only one protein-coding gene, KLF4.…”

“…2 and Supplementary Table 2. There are two previous deletions that overlap with the one encountered in our proband and are associated with delayed puberty or CHH ( 11 , 15 ). Ramineni et al reported a family, in which a deletion in 9q31.2 segregated with delayed puberty.…”

“…To date, 25 patients with Weiss–Kruszka syndrome have been reported ( 3 , 4 , 5 , 6 ), yet delayed puberty, anosmia, or CHH are not among the listed phenotypic features. On the other hand, deletions in the 9q31.2 chromosomal area have been continuously described since the 1970s ( 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ), at least one of whom had CHH ( 11 ), olfactory bulb hypoplasia ( 14 ), or delayed puberty in multiple family members ( 15 ), and at least four had cleft lip or palate ( 8 , 10 , 13 , 14 ), that is, phenotypic features reminiscent of KS. However, no clear link between the 9q31.2 deletions and complete KS currently exists.…”

Further characterization of the 9q31 microdeletion phenotype; delineation of a common region of overlap containing ZNF462

“…We present three patients with intellectual disability/global developmental delay and craniofacial dysmorphisms with interstitial deletions of the 9q31 chromosome region. Deletions in this region are relatively uncommon and there have been less than three dozen cases reported in the literature (Cao et al, 2015; Chien et al, 2010; Dugan et al, 2018; Gamerdinger et al, 2008; Iivonen et al, 2021; Mucciolo et al, 2014; Ramineni et al, 2019; Xu et al, 2013) and DECIPHER database (Firth et al, 2009) (DECIPHER ID: 270439, 250,887, 261,011, 253,228, 256,779, 286,220, 280,899, 252,795, 267,903, 296,377, 248,259, 274,871, 359,751, 394,934, 402,156, 402,516) (Figure 2). Common craniofacial dysmorphisms in this cohort include bilateral ptosis, arched eyebrows, a broad nasal root, low forehead, low set ears, anteverted nares, palate abnormalities, and a long philtrum.…”

“…Emerging information about one of these interstitial microdeletions (9q31) suggests that the haploinsufficiency of this region may cause a recognizable microdeletion syndrome. To date there have been several cases reported in the literature (Cao et al, 2015; Chien et al, 2010; Dugan et al, 2018; Gamerdinger et al, 2008; Iivonen et al, 2021; Mucciolo et al, 2014; Ramineni et al, 2019) and over a dozen additional cases recorded in DECIPHER (Firth et al, 2009). These cases share many phenotypic similarities such as developmental delay/intellectual disability, hearing loss, short stature/growth retardation, microcephaly (<10th percentile) and distinctive facial features of ptosis, arched eyebrows, and ear malformations.…”