Seckel Syndrome 7

A number sign (#) is used with this entry because of evidence that Seckel syndrome-7 (SCKL7) is caused by compound heterozygous mutation in the NIN gene (608684) on chromosome 14q22.

For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Clinical Features

Dauber et al. (2012) reported 2 sisters, 22 years and 18 years of age, who had severe pre- and postnatal growth retardation, microcephaly, and developmental delay. Both were given growth hormone but had suboptimal response, with resultant severe short stature as adults (-7.35 SD and -8.63 SD). In their late teens, both sisters had primary amenorrhea, Tanner 1 breast development, and Tanner 5 pubic hair, with normal LH and FSH levels and borderline low serum estradiol; pelvic ultrasound revealed small to relatively normal ovarian volume and a prepubertal uterus, and both were started on estrogen replacement therapy. Thyroid function tests showed borderline central hypothyroidism, and with worsening obesity in the sisters, they were started on thyroid hormone therapy. Other medical problems common to both sibs included congenital bilateral hip dysplasia, seizures that developed in infancy and were controlled by medication, and severe microcephaly (-6.8 SD and -6.7 SD) with severe mental retardation (preschool level). MRI of the brain at 20 years of age in the older sister showed cerebral hemispheres affected more severely than the cerebellum, with a slightly immature sulcation pattern, but there were no gross malformations.

Molecular Genetics

In 2 sisters with severe short stature, microcephaly, and developmental delay, whose parents were unaffected and appeared to be distantly related by whole-genome SNP genotyping, Dauber et al. (2012) performed whole-exome sequencing, followed by filtering that yielded 616 rare autosomal SNPs, from which 6 candidate genes were identified. Sanger sequencing of the most functionally probable gene, NIN (608684), revealed that the sisters were compound heterozygous for 2 rare missense variants, Q1222R (608684.0001) and N1709S (608684.0002). The parents were each heterozygous for one of the mutations, neither of which was present in the dbSNP or NHLBI exome variant server databases; however, the Q1222R variant was present in the 1000 Genomes pilot data, with an overall minor allele frequency of 0.001.

Animal Model

Dauber et al. (2012) performed morpholino knockdown of ninein (nin) in zebrafish and observed defects in the anterior neuroectoderm that resulted in a deformity of the developing cranium, with a small, squared skull highly reminiscent of the human phenotype.