ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10935639 Van Esch et al. (2000) reported five families with hypoparathyroidism, sensorineural deafness and renal anomaly (HDR). Patient 26/99 had a de novo intragenic deletion in exon 3 (465-513 deletion) resulting in a frameshift from codon 156. The predicted effect is a premature stop at codon 178 producing a truncated protein with loss of both zinc finger domains (ZF1 and ZF2). Both mother and son in family 12/99 had a nonsense mutation in exon 4 (828C>T) producing an amino acid change (R277X), which resulted in a truncated protein with loss of ZF1 and ZF2. Notably, there was no renal anomaly in either mother or son for family 12/99. The authors also reported Patient 3/99, who had an intragenic deletion in exon 5 (946-957 deletion) leading to an in-frame deletion of codons 316-319, which resulted in loss of four amino acids (TSCA) and disruption of ZF2 (no segregation data available). There were also two additional families with larger deletions, including GATA3 gene, that involved several other genes (Patient 5/99 with no segregation data - 900kb deletion; Family 23/99 with four affected members - 250kb deletion) and so they won't be considered as evidence for GATA3 gene loss-of-function.
11389161 Muroya et al. (2001) reported nine Japanese families with HDR syndrome. Family F (proband II.2; father I.1; and daughter III.1) had a heterozygous mutation at exon 4 (900insAA plus 901insCCT or C901AACCCT) that resulted in a premature stop at codon 357 with loss of the ZF2 domain. The mutation was absent in normal family members. In family G, a heterozygous nonsense mutation at exon 6 (C1099T, R367X) was detected in only affected family members (proband II.2 and daughter III.2). Other families in this report (A-D) had larger deletions that included genes other than GATA3 so they won't be considered as evidence of loss-of-function. Other variants reported in this study include: Family E (proband III.1) had a heterozygous missense mutation within the ZF1 domain of exon 4 (T823A, W275R). However, no other clinically affected family members were tested and given that it was a substitution, the author cannot exclude this mutation as a polymorphism.
27387476 Belge et al. (2017) reported eight patients in 5 families with clinical characteristics of HDR syndrome. In family 1, patient 1 (proband II.2) and patient 2 (mother I.2) had a heterozyogous deletion of 16 nucleotides (c.924+4_924+19del) within exon-intron 4 junction of GATA3 gene. RNA sequencing study showed the deletion had produced a shorter transcript-lacking exon 4 as a result of an incorrect splicing. In family 3, a heterozygous variant (c.1051-2A>G) was identified in patient 4 (II.3), which was within the AG acceptor site and predicted to cause exon 6 skipping (no RNA study was done; parents had no phenotype). Other variants reported in this study include: Patient 3 (II.1) from family 2 (deceased parents) had a c.896G>A (p.Arg299Gly) variant, which was predicted to be deleterious by in-silico algorithms due to a modification of the amino acid sequence of the linker region. Furthermore, a heterozygous substitution c.856A>G (p.N286D) was detected in patient 5 (II.1; deceased parents) and her two affected daughters (patient 6 - III.1 and patient 7 - III.2) in family 4. The variant involved a highly conserved amino acid within ZF1, which directly affected ZF1 polarity (affinity) and was predicted to be pathogenic by in-silico software. Patient 8 (II.1) from family 5 had a heterozygous substitution c.1017C>G (p.C339W) affecting the cysteine residue (within ZF2 domain) that interacts with the Zinc ion (deceased father; mother had no medical history). This study also had demonstrated that HDR syndrome might be associated with highly variable inter- and intra-familial phenotype.

Haploinsufficiency phenotype comments:

Doneray et al. (2015) reported a 2 month old Turkish boy with hypoparathyroidism, proteinuria and haematuria. There was no evidence of sensorineural deafness at the time of diagnosis (possibly due to variable in age of onset). A de novo nonsense mutation was detected in exon 6 (p.R367X; c.1099C>T) of GATA3 gene, which would produce a premature stop at codon 367. As such, the mutation has affected the zinc finger 2 domain leading to an absence of DNA-binding. This heterozygous p.R367X mutation was previously reported in three other HDR cases (PMID: 11389161, 14985365 and 19253381). Kita et al. (2019) reported a 6 year old girl (III-3) with hypocalcemia, hyperphosphatemia, hypoparathyroidism, vitamin D deficiency, bilateral congenital choanal atresia, bilataeral basal ganglia calcification, sensorineural hearing loss and bilateral multicystic dysplastic kidneys. Sanger sequencing identified a null variant NM_001002295.1:c.708_709insC (p.Ser237Glnfs*66) at exon 3 producing a loss of both zinc fingers (ZF1 and ZF2), which resulted in a premature stop at exon 4. Other family members also had the same null variant (mother II-3, grandfather I-2, half-sibling brother III-2 and brother III-5). The severity and clinical features were noted to be variable among the affected family members. The null variant was not seen in two unaffected family members (Half-sibling brother III-1 and brother III-4).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity