#309610
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that Prieto syndrome (PRS) is caused by hemizygous mutation in the WNK3 gene (300358) on chromosome Xp11.
Prieto syndrome (PRS) is an X-linked intellectual developmental disorder characterized by mildly to severely impaired intellectual development, developmental delay, autism spectrum disorder, or neuropsychiatric symptoms, variably accompanied by speech delay, epilepsy, microcephaly, structural brain defects, and minor facial anomalies (summary by Kury et al., 2022).
Prieto et al. (1987) described 8 males in 3 sibships who had a growth syndrome characterized by impaired intellectual development (ID), facial dysmorphism, abnormal dental growth, skin dimple at the lower back, clinodactyly, patella luxation, and subcortical cerebral atrophy.
Kury et al. (2022) described 14 males with impaired intellectual development from 6 unrelated families, including the large multigenerational family originally reported by Prieto et al. (1987). The patients were identified after molecular testing revealed mutations in the WNK3 gene. The 6 probands were referred for genetic testing for impaired intellectual development, developmental delay (DD), autism spectrum disorder, or neuropsychiatric symptoms. In all families, tested mothers were asymptomatic heterozygotes. The most frequently reported features were ID and DD (14/14). Ten of 13 patients (77%) had minor dysmorphic features, but no unifying facial gestalt was evident. Five of 13 patients (38%) had behavioral or neuropsychiatric symptoms, including attention deficit-hyperactivity disorder (ADHD; 2 patients), autistic features (1 patient), and self-aggression (1 patient). Six of 13 patients (46%) exhibited mild microcephaly with head circumference between -2 SD and -2.4 SD. Five of 13 patients (38%) had epilepsy. Variable structural brain abnormalities were noted in 7/10 patients who had undergone MRI imaging, including 2 brothers from family 2 with polymicrogyria.
The transmission pattern of Prieto syndrome in the family reported by Prieto et al. (1987) was consistent with X-linked recessive inheritance.
In a study of the same Spanish family reported by Prieto et al. (1987), Watty et al. (1991) concluded that the locus may lie between DXS255 (at Xp11.22) and DXS84 (at Xp21.1).
Through international data sharing, Kury et al. (2022) identified 6 different maternally-inherited hemizygous loss-of-function missense mutations in the WNK3 gene in 14 male patients from 6 unrelated families with Prieto syndrome (see, e.g., 300358.0001-300358.0004). The families included the original large family (family 4) described by Prieto et al. (1987) in which genome sequencing identified a missense mutation (L300S; 300358.0001), which cosegregated with the disease phenotype over 3 generations in 6 affected males and 5 asymptomatic heterozygous mothers. Another missense variant (P204R; 300358.0002) was detected in family 2 with 3 affected males with ID/DD (3/3) and polymicrogyria (2/3). In family 3 with 1 affected male with mild ID and ADHD and 2 unaffected carrier females, a premature termination was detected (R241X; 300258.0003). In family 5 with 2 affected brothers, an intronic mutation disrupted a canonical splice site (300258.0004).
Kury, S., Zhang, J., Besnard, T., Caro-Llopis, A., Zeng, X., Robert, S. M., Josiah, S. S., Kiziltug, E., Denomme-Pichon, A. S., Cogne, B., Kundishora, A. J., Hao, L. T., and 68 others. Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genet. Med. 24: 1941-1951, 2022. [PubMed: 35678782, related citations] [Full Text]
Prieto, F., Badia, L., Mulas, F., Monfort, A., Mora, F. X-linked dysmorphic syndrome with mental retardation. Clin. Genet. 32: 326-334, 1987. [PubMed: 3121220, related citations] [Full Text]
Watty, A., Prieto, F., Beneyto, M., Neugebauer, M., Gal, A. Gene localization in a family with X-linked syndromal mental retardation (Prieto syndrome). Am. J. Med. Genet. 38: 234-239, 1991. [PubMed: 1673297, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 2958; DO: 0060805;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.22 | Prieto syndrome | 309610 | X-linked recessive | 3 | WNK3 | 300358 |
A number sign (#) is used with this entry because of evidence that Prieto syndrome (PRS) is caused by hemizygous mutation in the WNK3 gene (300358) on chromosome Xp11.
Prieto syndrome (PRS) is an X-linked intellectual developmental disorder characterized by mildly to severely impaired intellectual development, developmental delay, autism spectrum disorder, or neuropsychiatric symptoms, variably accompanied by speech delay, epilepsy, microcephaly, structural brain defects, and minor facial anomalies (summary by Kury et al., 2022).
Prieto et al. (1987) described 8 males in 3 sibships who had a growth syndrome characterized by impaired intellectual development (ID), facial dysmorphism, abnormal dental growth, skin dimple at the lower back, clinodactyly, patella luxation, and subcortical cerebral atrophy.
Kury et al. (2022) described 14 males with impaired intellectual development from 6 unrelated families, including the large multigenerational family originally reported by Prieto et al. (1987). The patients were identified after molecular testing revealed mutations in the WNK3 gene. The 6 probands were referred for genetic testing for impaired intellectual development, developmental delay (DD), autism spectrum disorder, or neuropsychiatric symptoms. In all families, tested mothers were asymptomatic heterozygotes. The most frequently reported features were ID and DD (14/14). Ten of 13 patients (77%) had minor dysmorphic features, but no unifying facial gestalt was evident. Five of 13 patients (38%) had behavioral or neuropsychiatric symptoms, including attention deficit-hyperactivity disorder (ADHD; 2 patients), autistic features (1 patient), and self-aggression (1 patient). Six of 13 patients (46%) exhibited mild microcephaly with head circumference between -2 SD and -2.4 SD. Five of 13 patients (38%) had epilepsy. Variable structural brain abnormalities were noted in 7/10 patients who had undergone MRI imaging, including 2 brothers from family 2 with polymicrogyria.
The transmission pattern of Prieto syndrome in the family reported by Prieto et al. (1987) was consistent with X-linked recessive inheritance.
In a study of the same Spanish family reported by Prieto et al. (1987), Watty et al. (1991) concluded that the locus may lie between DXS255 (at Xp11.22) and DXS84 (at Xp21.1).
Through international data sharing, Kury et al. (2022) identified 6 different maternally-inherited hemizygous loss-of-function missense mutations in the WNK3 gene in 14 male patients from 6 unrelated families with Prieto syndrome (see, e.g., 300358.0001-300358.0004). The families included the original large family (family 4) described by Prieto et al. (1987) in which genome sequencing identified a missense mutation (L300S; 300358.0001), which cosegregated with the disease phenotype over 3 generations in 6 affected males and 5 asymptomatic heterozygous mothers. Another missense variant (P204R; 300358.0002) was detected in family 2 with 3 affected males with ID/DD (3/3) and polymicrogyria (2/3). In family 3 with 1 affected male with mild ID and ADHD and 2 unaffected carrier females, a premature termination was detected (R241X; 300258.0003). In family 5 with 2 affected brothers, an intronic mutation disrupted a canonical splice site (300258.0004).
Kury, S., Zhang, J., Besnard, T., Caro-Llopis, A., Zeng, X., Robert, S. M., Josiah, S. S., Kiziltug, E., Denomme-Pichon, A. S., Cogne, B., Kundishora, A. J., Hao, L. T., and 68 others. Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genet. Med. 24: 1941-1951, 2022. [PubMed: 35678782] [Full Text: https://doi.org/10.1016/j.gim.2022.05.009]
Prieto, F., Badia, L., Mulas, F., Monfort, A., Mora, F. X-linked dysmorphic syndrome with mental retardation. Clin. Genet. 32: 326-334, 1987. [PubMed: 3121220] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03297.x]
Watty, A., Prieto, F., Beneyto, M., Neugebauer, M., Gal, A. Gene localization in a family with X-linked syndromal mental retardation (Prieto syndrome). Am. J. Med. Genet. 38: 234-239, 1991. [PubMed: 1673297] [Full Text: https://doi.org/10.1002/ajmg.1320380213]
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