PMC8585740_01
Pedigree of the Czech family with ATS-ID syndrome. Proband (IV-1) and his maternal uncle (III-5) have hemizygous deletion in Xq22.3; the mother (III-4) and grandmother (II-4) are heterozygous for deletion Xq22.3.
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F1
The proband (Figure 1: IV-1) was born at 37 weeks of gestation with birth weight of 3,200 g and length of 48 cm.
Proband: (A) Short after birth. (B) At 2 years of age with mother. Maternal uncle: (C) At 10 months of age. (D) At 17 years of age. (E) At 20 years of age.
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F2
He was born with glucosuria, hyperbilirubinemia, pulmonary hypertension, and dysmorphic features, including flat midface, hypertelorism, antimongoloid slants, deep-set eyes, synophrys, anteverted nares, hypoplastic nasal bones, downturned corners of mouth, sparse hair, palmar crease, cutaneous syndactyly of two to three fingers, micropenis, cryptorchidism, cutis marmorata, and hypertrichosis (Figures 2C-E).
PMC8585740_02
Proband: (A) Short after birth. (B) At 2 years of age with mother. Maternal uncle: (C) At 10 months of age. (D) At 17 years of age. (E) At 20 years of age.
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F2
He was born with glucosuria, hyperbilirubinemia, pulmonary hypertension, and dysmorphic features, including flat midface, hypertelorism, antimongoloid slants, deep-set eyes, synophrys, anteverted nares, hypoplastic nasal bones, downturned corners of mouth, sparse hair, palmar crease, cutaneous syndactyly of two to three fingers, micropenis, cryptorchidism, cutis marmorata, and hypertrichosis (Figures 2C-E).
Chromosomal deletion del(X) (q22.3q23) detected by whole-exome sequencing and array-comparative genome hybridization (CGH). Upper panel shows genomic profiles of the proband, father, and mother. Log2 ratio (L2R) track represents the copy-number profile indicating a maternally inherited hemizygous deletion in the male proband. Gray dots mark sequencing targets without any copy number abnormality. Red and green dots indicate the presence of losses and gains, respectively. Areas with light blue background show loss of heterozygosity regions predicted by zygosity status as shown in the allele frequency (AF) plot. In the AF track, black dots represent SNPs with a single allele detected in the sequencing reads, and green and red dots highlight SNPs with two alleles found in approximately 1:1 and another ratio, respectively. Lower panel contains the Database of Genomic Variants (DGV) and RefSeq gene annotation database. Color intensity within the DGV track corresponds to the level of population variability, green for losses, red for gains, and purple for complex regions.
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F3
In addition, two different segmentation algorithms for copy number variation (CNV) evaluation identified a Xq22.3q23 deletion of size approximately 2.91 Mb in the proband and his asymptomatic mother (Figure 3).
FISH evaluations of the delXq22.3 region. (A) Metaphase chromosomes from the mother (III-4) showed FISH signal for the Xq22.3 region obtained using probe RP1-31B8 (green) on only one X chromosome. Probe for X chromosome centromeric region (RP13-34C21:red) showed FISH signals in both chromosomes. (B) Metaphase chromosomes from the proband (IV-I) showed no FISH signal for the Xq22.3 region and only one signal for the X chromosome centromeric region.
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F4
FISH analysis using a probe RP1-31B8 (108,414,862-108,517,413), which spans the proximal region of GUCY2F gene, confirmed the deletion in the proband and in the affected maternal uncle (IIII-5) (Figure 4B). The mother (III-4) and grandmother (II-4) were shown to be the carriers of the Xq22.3 deletion (Figure 4A), and the sister of the grandmother (II-5) was negative.