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

Abstract

Patients with deletions in chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with patient’s Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2), but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

“…6 B) ( Niehrs and Meinhardt, 2002 ; Scholpp et al, 2004 ) . When we examined the expression of 32 genes linked to CHH+anosmia ( Cho et al, 2019 ; Messina et al, 2020 ; Iivonen et al, 2021 ) after 2 days of FGF8, we found that ten of these genes to be differentially expressed ( ).…”

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.…”

A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers

“…The second strongest signal is observed for chromosome 9q31.2 (rs630965, p meta = 1.01 × 10 −63 ). Patients with deletions on 9q31.2 may have delayed puberty (Iivonen et al, 2021). The third strongest signal observed on BNC2 (rs3814113, p meta = 2.16 × 10 −43 ) is a putative tumor suppressor gene in highgrade serous ovarian carcinoma, which impacted cell survival after oxidative stress (Cesaratto et al, 2016).…”